Compounds, compositions and methods

ABSTRACT

The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and methods of making and using thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 62/805,263, filed Feb. 13, 2019 and62/877,232, filed Jul. 22, 2019, both of which are incorporated byreference in their entirety.

FIELD

The present disclosure relates generally to small molecule modulators ofeukaryotic initiation factor 2B and their use as therapeutic agents, forexample, in treating diseases mediated thereby such as Alzheimer's,Parkinson's, ALS, frontotemporal dementia, and cancer.

BACKGROUND

Neurodegenerative diseases, such as Parkinson's disease (PD),amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), andFrontotemporal dementia (FTD) have a negative effect on the lives ofmillions of people.

The multi-subunit protein complexes eukaryotic initiation factor 2B andeukaryotic initiation factor 2 are required for protein synthesisinitiation and regulation in eukaryotic cells. Eukaryotic initiationfactor 2B is composed of five subunits (α, β, γ, δ, and ε), andeukaryotic initiation factor 2 is composed of three subunits (α, β, andγ). Eukaryotic initiation factor 2B functions as a guanine nucleotideexchange factor (GEF) that catalyzes the exchange ofguanosine-5′-diphosphate (GDP) with guanosine-5′-triphosphate (GTP) oneukaryotic initiation factor 2, thereby allowing the GTP boundeukaryotic initiation factor 2 to bind to the initiating methioninetransfer RNA and initiate protein synthesis.

Eukaryotic initiation factor 2B is active when complexed as a tensubunit dimer. Eukaryotic initiation factor 2 is active when bound toGTP and inactive when bound to GDP. Moreover, when the a subunit ofeukaryotic initiation factor 2 is phosphorylated on serine 51, itinhibits and regulates the guanine nucleotide exchange activity ofeukaryotic initiation factor 2B. In its phosphorylated form, eukaryoticinitiation factor 2 remains in an inactive GDP bound state andtranslation initiation is blocked.

The interaction between eukaryotic initiation factor 2B and eukaryoticinitiation factor 2 plays an important role in the integrated stressresponse (ISR) pathway. Activation of this pathway leads in part to ATF4(Activating Transcription Factor 4) expression and stress granuleformation. Aberrant ISR activation is found in multipleneurodegenerative diseases, with a strong functional link to pathologycharacterized by the RNA-binding/stress-granule protein TAR DNA bindingprotein (TARDBP), also known as TDP43. Activation of eIF2B inhibits theISR and ISR dependent stress granule formation and is found to beneuroprotective in multiple disease models.

Impairment of eukaryotic initiation factor 2B activity is correlated toactivation of the ISR pathway that is implicated in a varietyneurodegenerative diseases including Parkinson's disease, amyotrophiclateral sclerosis (ALS), Alzheimer's disease, and frontotemporaldementia. Mutations in TDP43 and other RNA-bindingproteins/stress-granule proteins alter stress-granule dynamics and causeALS. Inhibition of the ISR pathway can block and promote the dissolutionof stress-granules. In addition, mutations in the human eukaryoticinitiation factor 2B subunits have been identified as causingleukoencephalopathy with vanishing white matter (VWM) and childhoodataxia with central nervous system hypomyelination (CACH). In VWM/CACHpatients, white matter lesions severely deteriorate and neurologicaldisorders are exacerbated after stresses, and their eukaryoticinitiation factor 2B guanine nucleotide exchange activities aregenerally lower than normal.

DESCRIPTION

Provided herein are compounds, or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug of the compounds, that are useful in treating and/or preventingdiseases mediated, at least in part, by eukaryotic initiation factor 2B,such as neurodegenerative diseases (e.g., neurodegeneration in priondisease) and cancer.

In some embodiments, provided are compounds that modulate the activityof eukaryotic initiation factor 2B. In some embodiments, the compoundsmodulate the regulation of eukaryotic initiation factor 2B. In someaspects, the compounds modulate the inhibition of eukaryotic initiationfactor 2B by phosphorylated eukaryotic initiation factor 2. In someembodiments, the compounds interfere with the interaction betweeneukaryotic initiation factor 2B and phosphorylated eukaryotic initiationfactor 2. In some embodiments, the phosphorylated eukaryotic initiationfactor 2 is phosphorylated on its alpha subunit (eukaryotic initiationfactor 2α phosphate).

In some embodiments, provided are compounds that act as activators ofeukaryotic initiation factor 2B by increasing its guanosinediphosphate/guanosine triphosphate (GDP/GTP) nucleotide exchangeactivity. In some embodiments, the compounds promote eukaryoticinitiation factor 2B dimer formation. In other embodiments, thecompounds enhances the guanine nucleotide exchange factor (GEF) activityof eukaryotic initiation factor 2B. In other embodiments, the compoundsincreases the guanine nucleotide exchange factor (GEF) activity ofeukaryotic initiation factor 2B on its eukaryotic initiation factor2/GDP substrate.

In some embodiments, provided are compounds that desensitizes cells tothe deleterious effects of eukaryotic initiation factor 2B inhibition.In some embodiments the deleterious effects include ATF4 expression andstress granule formation.

In another embodiment, provided is a pharmaceutical compositioncomprising a compound as described herein, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, and a pharmaceutically acceptablecarrier.

In another embodiment, provided is a method for treating a disease orcondition mediated, at least in part, by eukaryotic initiation factor2B, the method comprising administering an effective amount of thepharmaceutical composition comprising a compound as described herein, ora pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof.

In another embodiment, provided is a method for treating a disease orcondition mediated, at least in part, by regulation of eukaryoticinitiation factor 2B, the method comprising administering an effectiveamount of the pharmaceutical composition comprising a compound asdescribed herein, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, and a pharmaceutically acceptable carrier, to a subject in needthereof.

In another embodiment, provided is a method for promoting or stabilizingeukaryotic initiation factor 2B dimer formation, the method comprisingadministering an effective amount of the pharmaceutical compositioncomprising a compound as described herein, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, and a pharmaceutically acceptablecarrier, to a subject in need thereof.

In another embodiment, provided is a method for promoting eukaryoticinitiation factor 2B activity, the method comprising administering aneffective amount of the pharmaceutical composition comprising a compoundas described herein, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, and a pharmaceutically acceptable carrier, to a subject in needthereof.

In another embodiment, provided is a method for desensitizing cells toeukaryotic initiation factor 2 phosphorylation, the method comprisingadministering an effective amount of the pharmaceutical compositioncomprising a compound as described herein, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, and a pharmaceutically acceptablecarrier, to a subject in need thereof.

In another embodiment, provided is a method for inhibiting theintegrated stress response pathway, the method comprising administeringan effective amount of the pharmaceutical composition comprising acompound as described herein, or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof, and a pharmaceutically acceptable carrier, to a subjectin need thereof.

In another embodiment, provided is a method for inhibiting stressgranule formation, the method comprising administering an effectiveamount of the pharmaceutical composition comprising a compound asdescribed herein, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, and a pharmaceutically acceptable carrier, to a subject in needthereof.

In another embodiment, provided is a method for inhibiting ATF4expression, the method comprising administering an effective amount ofthe pharmaceutical composition comprising a compound as describedherein, or a pharmaceutically acceptable salt, isotopically enrichedanalog, stereoisomer, mixture of stereoisomers, or prodrug thereof, anda pharmaceutically acceptable carrier, to a subject in need thereof.

In another embodiment, provided is a method for inhibiting ATF4translation, the method comprising administering an effective amount ofthe pharmaceutical composition comprising a compound as describedherein, or a pharmaceutically acceptable salt, isotopically enrichedanalog, stereoisomer, mixture of stereoisomers, or prodrug thereof, anda pharmaceutically acceptable carrier, to a subject in need thereof.

The disclosure also provides compositions, including pharmaceuticalcompositions, kits that include the compounds, and methods of using (oradministering) and making the compounds. The disclosure further providescompounds or compositions thereof for use in a method of treating adisease, disorder, or condition that is mediated, at least in part, byeukaryotic initiation factor 2B. Moreover, the disclosure provides usesof the compounds or compositions thereof in the manufacture of amedicament for the treatment of a disease, disorder, or condition thatis mediated, at least in part, by eukaryotic initiation factor 2B.

DETAILED DESCRIPTION

The following description sets forth exemplary embodiments of thepresent technology. It should be recognized, however, that suchdescription is not intended as a limitation on the scope of the presentdisclosure but is instead provided as a description of exemplaryembodiments.

1. Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line or a dashed line drawn through a line in astructure indicates a specified point of attachment of a group. Unlesschemically or structurally required, no directionality orstereochemistry is indicated or implied by the order in which a chemicalgroup is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to12 carbon atoms (i.e., C₁₋₁₂ alkyl), 1 to 8 carbon atoms (i.e., C_(1_8)alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl) or 1 to 4 carbon atoms(i.e., C₁₋₄ alkyl). Examples of alkyl groups include, e.g., methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. When an alkyl residue having a specific number ofcarbons is named by chemical name or identified by molecular formula,all positional isomers having that number of carbons may be encompassed;thus, for example, “butyl” includes n-butyl (i.e., —(CH₂)₃CH₃),sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e., —CH₂CH(CH₃)₂), andtert-butyl (i.e., —C(CH₃)₃); and “propyl” includes n-propyl (i.e.,—(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having a triple bond and a doublebond, such as one triple bond and one double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Alkylthio” refers to the group “alkyl-S—”. “Alkylsulfinyl” refers tothe group “alkyl-S(O)—”. “Alkylsulfonyl” refers to the group“alkyl-S(O)₂—”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)₂-alkyl.

“Acyl” refers to a group —C(O)R^(y), wherein R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of acyl include, e.g., formyl, acetyl,cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein, or R^(y) and R^(z) are taken together to form a cycloalkyl orheterocyclyl; each of which may be optionally substituted, as definedherein.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Aminoalkyl” refers to the group “-alkyl-NR^(y)R^(z),” wherein R^(y) andR^(z) are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Amidino” refers to —C(NR^(y))(NR^(z) ₂), wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however,does not encompass or overlap in any way with heteroaryl defined below.If one or more aryl groups are fused with a heteroaryl, the resultingring system is heteroaryl. If one or more aryl groups are fused with aheterocyclyl, the resulting ring system is heterocyclyl.

“Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein.

“Carboxyl ester” or “ester” refer to both —OC(O)R^(x) and —C(O)OR^(x),wherein R^(x) is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroalkyl, or heteroaryl; each of which may be optionallysubstituted, as defined herein.

“Cyanoalkyl” refers to refers to an alkyl group as defined above,wherein one or more (e.g., 1 or 2) hydrogen atoms are replaced by acyano (—CN) group.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e., the cyclic group having at least one double bond) andcarbocyclic fused ring systems having at least one sp³ carbon atom(i.e., at least one non-aromatic ring). As used herein, cycloalkyl hasfrom 3 to 20 ring carbon atoms (i.e., C₃₋₂₀ cycloalkyl), 3 to 12 ringcarbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10 ring carbon atoms (i.e.,C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl), or3 to 6 ring carbon atoms (i.e., C₃_₆ cycloalkyl). Monocyclic groupsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic groups include, for example,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further,the term cycloalkyl is intended to encompass any non-aromatic ring whichmay be fused to an aryl ring, regardless of the attachment to theremainder of the molecule. Still further, cycloalkyl also includes“spirocycloalkyl” when there are two positions for substitution on thesame carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, orspiro[5.5]undecanyl.

“Cycloalkoxy” refers to “—O-cycloalkyl.”

“Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

“Cycloalkylalkoxy” refers to “—O-alkyl-cycloalkyl.”

“Guanidino” refers to —NR^(y)C(═NR^(z))(NR^(y)R^(z)), wherein each R^(y)and R^(z) are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein.

“Hydrazino” refers to —NHNH₂.

“Imino” refers to a group —C(NR^(y))R^(z), wherein R^(y) and R^(z) areeach independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Imido” refers to a group —C(O)NR^(y)C(O)R^(z), wherein R^(y) and R^(z)are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Halogen” or “halo” refers to atoms occupying group VIIA of the periodictable, such as fluoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms arereplaced by a halogen. For example, where a residue is substituted withmore than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached. Dihaloalkyland trihaloalkyl refer to alkyl substituted with two (“di”) or three(“tri”) halo groups, which may be, but are not necessarily, the samehalogen. Examples of haloalkyl include, e.g., trifluoromethyl,difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

“Hydroxyalkyl” refers to an alkyl group as defined above, wherein one ormore (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxygroup.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group, provided thepoint of attachment to the remainder of the molecule is through a carbonatom. The term “heteroalkyl” includes unbranched or branched saturatedchain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbonatoms may be independently replaced with the same or differentheteroatomic group. Heteroatomic groups include, but are not limited to,—NR^(y)—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, wherein R^(y) ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein. Examples of heteroalkyl groups include, e.g., ethers(e.g., —CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃, etc.),thioethers (e.g., —CH₂SCH₃, —CH(CH₃)SCH₃, —CH₂CH₂SCH₃,—CH₂CH₂SCH₂CH₂SCH₃, etc.), sulfones (e.g., —CH₂S(O)₂CH₃,—CH(CH₃)S(O)₂CH₃, —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)₂CH₂CH₂OCH₃, etc.), andamines (e.g., —CH₂NR^(y)CH₃, —CH(CH₃)NR^(y)CH₃, —CH₂CH₂NR^(y)CH₃,—CH₂CH₂NR^(y)CH₂CH₂NR^(y)CH₃, etc., where R^(y) is independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein). As used herein, heteroalkyl includes 1 to 10 carbonatoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroalkylene” refers to a divalent alkyl group (i.e., alkylene) inwhich one or more (e.g., one to five or one to three) of the carbonatoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group, provided thatwhen L is heteroalkylene then the point of attachment of theheteroalkylene to the pyran is through a carbon atom. “Heteroalkylene”groups must have at least one carbon and at least one heteroatomic groupwithin the chain. Further to when L is heteroalkylene, the point ofattachment of the heteroalkylene to —R² may be through a carbon atom ora heteroatom. The term “heteroalkylene” includes unbranched or branchedsaturated chain having carbon and heteroatoms. By way of example, 1, 2,or 3 carbon atoms may be independently replaced with the same ordifferent heteroatomic group. Heteroatomic groups include, but are notlimited to, —NR^(y)—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, whereinR^(y) is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroalkyl, or heteroaryl; each of which may be optionallysubstituted, as defined herein. Examples of heteroalkylene groupsinclude, e.g., —CH₂OCH₂—, —CH(CH₃)OCH₂—, —CH₂CH₂OCH₂—,—CH₂CH₂OCH₂CH₂OCH₂—, —CH₂SCH₂—, —CH(CH₃)SCH₂—, —CH₂CH₂SCH₂—,—CH₂CH₂SCH₂CH₂SCH₂—, —CH₂S(O)₂CH₂—, —CH(CH₃)S(O)₂CH₂—, —CH₂CH₂S(O)₂CH₂—,—CH₂CH₂S(O)₂CH₂CH₂OCH₂—, —CH₂NR^(y)CH₂—, —CH(CH₃)NR^(y)CH₂—,—CH₂CH₂NR^(y)CH₂—, —CH₂CH₂NR^(y)CH₂CH₂NR^(y)CH₂—, etc., where R^(y) ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein). As used herein, heteroalkylene includes 1 to 10carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, theterm “heteroalkylene” does not include groups such as amides or otherfunctional groups having an oxo present on one or more carbon atoms.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃_heteroaryl), and 1 to 5 ring heteroatoms,1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ringheteroatoms, or 1 ring heteroatom independently selected from nitrogen,oxygen, and sulfur. In certain instances, heteroaryl includes 5-10membered ring systems, 5-7 membered ring systems, or 5-6 membered ringsystems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, oxygen, and sulfur. Examples of heteroarylgroups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl,benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl,benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl),benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, imidazolyl, indazolyl,indolyl, isoindolyl, isoquinolyl, isoxazolyl, isothiazolyl,naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, thiazolyl, thiadiazolyl, triazolyl,tetrazolyl, and triazinyl. Examples of the fused-heteroaryl ringsinclude, but are not limited to, benzo[d]thiazolyl, quinolinyl,isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl,pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where theheteroaryl can be bound via either ring of the fused system. Anyaromatic ring, having a single or multiple fused rings, containing atleast one heteroatom, is considered a heteroaryl regardless of theattachment to the remainder of the molecule (i.e., through any one ofthe fused rings). Heteroaryl does not encompass or overlap with aryl asdefined above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

“Heterocyclyl” refers to a saturated or partially unsaturated cyclicalkyl group, with one or more ring heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. The term “heterocyclyl” includesheterocycloalkenyl groups (i.e., the heterocyclyl group having at leastone double bond), bridged-heterocyclyl groups, fused-heterocyclylgroups, and spiro-heterocyclyl groups. A heterocyclyl may be a singlering or multiple rings wherein the multiple rings may be fused, bridged,or spiro, and may comprise one or more (e.g., 1 to 3) oxo (═O) orN-oxide (—O—) moieties. Any non-aromatic ring containing at least oneheteroatom is considered a heterocyclyl, regardless of the attachment(i.e., can be bound through a carbon atom or a heteroatom). Further, theterm heterocyclyl is intended to encompass any non-aromatic ringcontaining at least one heteroatom, which ring may be fused to an arylor heteroaryl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 ring carbon atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 ring carbonatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e.,C_(3-s) heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms,1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomindependently selected from nitrogen, sulfur, or oxygen. Examples ofheterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl,benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl,hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl,imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl,phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl,pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl,tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e.,thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes“spiroheterocyclyl” when there are two positions for substitution on thesame carbon atom. Examples of the spiro-heterocyclyl rings include,e.g., bicyclic and tricyclic ring systems, such asoxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.Examples of the fused-heterocyclyl rings include, but are not limitedto, 1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-.”

“Oxime” refers to the group —CR^(y)(═NOH) wherein R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein.

“Sulfonyl” refers to the group —S(O)₂R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,phenylsulfonyl, and toluenesulfonyl.

“Sulfinyl” refers to the group —S(O)R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl,phenylsulfinyl, and toluenesulfinyl.

“Sulfonamido” refers to the groups —SO₂NR^(y)R^(z) and —NR^(y)SO₂R^(z),where R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;each of which may be optionally substituted, as defined herein.

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, a divalent heteroaryl group, etc., may also be referred toas an “alkylene” group or an “alkylenyl” group (for example, methylenyl,ethylenyl, and propylenyl), an “arylene” group or an “arylenyl” group(for example, phenylenyl or napthylenyl, or quinolinyl forheteroarylene), respectively. Also, unless indicated explicitlyotherwise, where combinations of groups are referred to herein as onemoiety, e.g., arylalkyl or aralkyl, the last mentioned group containsthe atom by which the moiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogenatoms on the designated atom or group may or may not be replaced by amoiety other than hydrogen.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) whereinat least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by abond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl,alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —NHNH₂, ═NNH₂, imino, imido, hydroxy, oxo, oxime,nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate,—S(O)OH, —S(O)₂OH, sulfonamido, thiol, thioxo, N-oxide, or —Si(R^(y))₃,wherein each R^(y) is independently hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

In certain embodiments, “substituted” includes any of the above alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groupsin which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms areindependently replaced with deuterium, halo, cyano, nitro, azido, oxo,alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR^(g)R^(h), —NR^(g)C(═O)R^(h), —NR^(g)C(═O)NR^(g)R^(h),—NR^(g)C(═O)OR^(h), —NR^(g)S(═O)₁₋₂R^(h), —C(═O)R^(g), —C(═O)OR^(g),—OC(═O)OR^(g), —OC(═O)R^(g), —C(═O)NR^(g)R^(h), −OC(═O)NR^(g)R^(h),—OR^(g), —SR^(g), —S(═O)R^(g), —S(═O)₂R^(g), —OS(═O)₁₋₂R^(g),—S(═O)₁₋₂R^(g), —NR^(g)S(═O)₁₋₂NR^(g)R^(h), ═NSO₂R^(g), ═NOR^(g),—S(═O)₁₋₂NR^(g)R^(h), —SF₅, —SCF₃, or —OCF₃. In certain embodiments,“substituted” also means any of the above groups in which one or more(e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with —C(═O)R^(g),—C(═O)OR^(g), —C(═O)NR^(g)R^(h), —CH₂SO₂R^(g), or —CH₂SO₂NR^(g)R^(h). Inthe foregoing, R^(g) and R^(h) are the same or different andindependently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In certainembodiments, “substituted” also means any of the above groups in whichone or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R^(g)and R^(h) and R^(i) are taken together with the atoms to which they areattached to form a heterocyclyl ring optionally substituted with oxo,halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl,or alkoxy.

Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.

In certain embodiments, as used herein, the phrase “one or more” refersto one to five. In certain embodiments, as used herein, the phrase “oneor more” refers to one to three.

Any compound or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.These forms of compounds may also be referred to as “isotopicallyenriched analogs.” Isotopically labeled compounds have structuresdepicted herein, except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated. Suchisotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The term “isotopically enriched analogs” includes “deuterated analogs”of compounds described herein in which one or more hydrogens is/arereplaced by deuterium, such as a hydrogen on a carbon atom. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half-life of any compound when administered to amammal, particularly a human. See, for example, Foster, “DeuteriumIsotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well knownin the art, for example by employing starting materials in which one ormore hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism, and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements, and/oran improvement in therapeutic index. An ¹⁸F, ³H, ¹¹C labeled compoundmay be useful for PET or SPECT or other imaging studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in a compound described herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino, and/orcarboxyl groups, or groups similar thereto.

Provided are also or a pharmaceutically acceptable salt, isotopicallyenriched analog, deuterated analog, stereoisomer, mixture ofstereoisomers, and prodrugs of the compounds described herein.“Pharmaceutically acceptable” or “physiologically acceptable” refer tocompounds, salts, compositions, dosage forms, and other materials whichare useful in preparing a pharmaceutical composition that is suitablefor veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids, and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic or organic acids. Salts derivedfrom inorganic acids include, e.g., hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include, e.g., acetic acid, propionic acid, gluconicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and thelike. Likewise, pharmaceutically acceptable base addition salts can beprepared from inorganic or organic bases. Salts derived from inorganicbases include, by way of example only, sodium, potassium, lithium,aluminum, ammonium, calcium, and magnesium salts. Salts derived fromorganic bases include, but are not limited to, salts of primary,secondary, and tertiary amines, such as alkyl amines (i.e., NH₂(alkyl)),dialkyl amines (i.e., HN(alkyl)₂), trialkyl amines (i.e., N(alkyl)₃),substituted alkyl amines (i.e., NH₂(substituted alkyl)), di(substitutedalkyl) amines (i.e., HN(substituted alkyl)₂), tri(substituted alkyl)amines (i.e., N(substituted alkyl)₃), alkenyl amines (i.e.,NH₂(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)₂), trialkenyl amines(i.e., N(alkenyl)₃), substituted alkenyl amines (i.e., NH₂(substitutedalkenyl)), di(substituted alkenyl) amines (i.e., HN(substitutedalkenyl)₂), tri(substituted alkenyl) amines (i.e., N(substitutedalkenyl)₃, mono-, di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl),HN(cycloalkyl)₂, N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e.,NH₂(aryl), HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examplesof suitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “hydrate” refers to the complex formed by the combining of acompound described herein and water.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the disclosure. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, andethanolamine.

Some of the compounds disclosed herein may exist as tautomers. Tautomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

Some of the compounds disclosed herein, or their pharmaceuticallyacceptable salts, may include an asymmetric center and may thus giverise to enantiomers, diastereomers, and other stereoisomeric forms thatmay be defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)- for amino acids. The present disclosure is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. Optically active (+) and (−), (R)- and (S)-, or(D)- and (L)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, for example,chromatography and/or fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centres of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers, or mixtures thereof, and includes “enantiomers,”which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

“Diastereomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

Relative centers of the compounds as depicted herein are indicatedgraphically using the “thick bond” style (bold or parallel lines) andabsolute stereochemistry is depicted using wedge bonds (bold or parallellines).

“Prodrugs” means any compound which releases an active parent drugaccording to a structure described herein in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of a compound describedherein are prepared by modifying functional groups present in thecompound described herein in such a way that the modifications may becleaved in vivo to release the parent compound. Prodrugs may be preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to the parent compounds. Prodrugs include compounds describedherein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in acompound described herein is bonded to any group that may be cleaved invivo to regenerate the free hydroxy, amino, or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited toesters (e.g., acetate, formate, and benzoate derivatives), amides,guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds described herein, and the like.Preparation, selection, and use of prodrugs is discussed in T. Higuchiand V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of theA.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. EdwardB. Roche, American Pharmaceutical Association and Pergamon Press, 1987,each of which are hereby incorporated by reference in their entirety.

2. Compounds

Provided herein are compounds that are modulators of eukaryoticinitiation factor 2B. In certain embodiments, provided is a compound ofFormula I:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:

ring A is cycloalkyl or heterocyclyl, provided ring A is not abicyclo[1.1.1]pentane or bicyclo[2.1.1]hexane; wherein each isoptionally substituted with one to six R¹⁴;

ring B is a 5- or 6-membered heteroaryl or phenyl; wherein each isoptionally substituted with one to three R¹³;

Q¹ and Q² are each independently O, S or NR¹⁵;

L is a C₁₋₆ alkylene linker, optionally substituted with one to threesubstituents independently selected from halo, cyano, nitro, —OR⁶, —SR⁶,—SF₅, —NR⁶R⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R⁶, —C(O)OR⁶,—OC(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶,—S(O)₁₋₂NR⁶, —NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, and—NR⁶C(O)OR⁷;

z is 0 or 1;

X¹ is O, NR⁹ or a bond;

R¹ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, or heterocyclyl, each of which, other than hydrogen, isoptionally substituted with one to three R¹¹;

R² is C₁₋₆ haloalkyl;

R³ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other thanhydrogen, is optionally substituted with one to five R¹¹;

R⁴ and R⁵ are independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl orC₂₋₁₂ alkynyl, each of which, other than hydrogen, is independentlyoptionally substituted with one to five R¹;

or R³ and R⁴, together with the atoms to which they are attached, jointo form a C₃₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one to five R¹¹;

or R⁴ and R⁵, together with the atoms to which they are attached, jointo form a C₃₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one to five R¹¹;

each of R⁶, R⁷, and R⁸ is independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl,heteroaryl, —C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰R²¹, —S(O)₁₋₂R²⁰ or—S(O)₁₋₂NR²⁰, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R⁶, R⁷, and R is independentlyoptionally substituted with one to five R¹²; or two of R⁶, R⁷, and R⁸are taken together with the atoms to which they are attached to formheterocyclyl independently optionally substituted by one to three halo,oxo, or C₁₋₁₂ alkyl independently optionally substituted by one to threeoxo, halo, hydroxyl, or amino;

R⁹ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, or heterocyclyl, each of which, other than hydrogen, isoptionally substituted with one to three R¹¹;

each R¹¹ is independently halo, cyano, nitro, oxo, —OR⁶, —SR⁶, —SF₅,—NR⁶R⁷, C₁₋₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)R⁶, —C(O)OR⁶, —OC(O)OR⁶, —OC(O)R⁶,—C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶,—NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, or —NR⁶C(O)OR⁷, whereineach alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, andheteroaryl of R¹¹ is independently optionally substituted with one tofive R¹²;

each R¹² is independently halo, cyano, nitro, oxo, —OR³⁰, —SR³⁰, —SF₅,—NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰,—OC(O)R³⁰, —C(O)NR³⁰R³¹, —OC(O)NR³⁰R³¹, —NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰,—S(O)₁₋₂NR³⁰, —NR³⁰S(O)₁₋₂R³¹, —NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or—NR³⁰C(═O)OR³¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R² is independently optionallysubstituted with one to three halo or C₁₋₁₂ alkyl independentlyoptionally substituted by one to three oxo, halo, hydroxyl, or amino;

each R¹³ is independently halo, cyano, nitro, oxo, —OR³⁰, —SR³⁰, —SF₅,—NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰,—OC(O)R³⁰, —C(O)NR³⁰R³¹, —OC(O)NR³⁰R³¹, —NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰,—S(O)₁₋₂NR³⁰, —NR³⁰S(O)₁₋₂R³¹, —NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or—NR³⁰C(═O)OR³¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R¹³ is independently optionallysubstituted with one to three halo or C₁₋₁₂ alkyl independentlyoptionally substituted by one to three oxo, halo, hydroxyl, or amino;

each R¹⁴ is independently halo, cyano, —NR⁶R⁷, C₁₋₆ alkyl, C₁₋₆ alkoxy,or C₁₋₆ haloalkyl, or two R¹⁴ together with the atoms to which they areattached form a ring or a C═O;

each R¹⁵ is independently hydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

each R²⁰ and R²¹ is independently hydrogen or C₁₋₁₂ alkyl independentlyoptionally substituted with one to three oxo, halo, hydroxyl, or amino;or R²⁰ and R²¹ are taken together with the atoms to which they areattached to form heterocyclyl independently optionally substituted byone to three halo or C₁₋₁₂ alkyl independently optionally substituted byone to three oxo, halo, hydroxyl, or amino; and

each R³⁰ and R³¹ is independently hydrogen or C₁₋₁₂ alkyl independentlyoptionally substituted with one to three oxo, halo, hydroxyl, or amino;or R³⁰ and R³¹ are taken together with the atoms to which they areattached to form heterocyclyl independently optionally substituted byone to three halo or C₁₋₁₂ alkyl independently optionally substituted byone to three oxo, halo, hydroxyl, or amino.

In certain embodiments, ring A is C₃₋₁₀ cycloalkyl or heterocyclyl,provided ring A is not a bicyclo[1.1.1]pentane or bicyclo[2.1.1]hexane;wherein each is optionally substituted with one to six R¹⁴.

In certain embodiments, ring A is monocyclic cycloalkyl, fused bicycliccycloalkyl, or spiro bicyclic cycloalkyl, wherein each is optionallysubstituted with one to six R¹⁴. In certain embodiments, ring A ismonocyclic C₃₋₈ cycloalkyl, fused bicyclic C₄₋₁₀ cycloalkyl, or spiroC₄₋₁₀ bicyclic cycloalkyl, wherein each is optionally substituted withone to six R¹⁴.

In the embodiments disclosed herein, ring A is not optionallysubstituted bicyclo[1.1.1]pentane or optionally substitutedbicyclo[2.1.1]hexane, where the terms “bicyclo[1.1.1]pentane” and

“bicyclo[2.1.1]hexane” are represented by and, respectively.

In certain embodiments, ring A is heterocyclyl, wherein each isoptionally substituted with one to six R¹⁴.

In certain embodiments, each R⁴ is independently halo, cyano, —NR⁶R⁷,C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In certain embodiments, ring A is selected from:

wherein each is optionally substituted with one to four halo.

In certain embodiments, provided is a compound of Formula II:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:

p is 0, 1, 2, 3, 4, 5 or 6;

ring B is a 5- or 6-membered heteroaryl or phenyl, wherein each isoptionally substituted with one to three R¹³;

Q¹ and Q² are each independently O, S or NR¹¹;

L is a C₁₋₆ alkylene linker, optionally substituted with one to threesubstituents independently selected from halo, cyano, nitro, —OR⁶, —SR,—SF₅, —NR⁶R⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R⁶, —C(O)OR⁶,—OC(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶,—S(O)₁₋₂NR⁶, —NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, and—NR⁶C(O)OR⁷;

z is 0 or 1;

X¹ is O, NR⁹ or a bond;

R¹ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, or heterocyclyl, each of which, other than hydrogen, isoptionally substituted with one to three R¹¹;

R² is C₁₋₆ haloalkyl;

R³ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other thanhydrogen, is optionally substituted with one to five R¹¹;

R⁴ and R⁵ are independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl orC₂₋₁₂ alkynyl, each of which, other than hydrogen, is independentlyoptionally substituted with one to five R¹;

or R³ and R⁴, together with the atoms to which they are attached, jointo form a C₃₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one to five R¹¹;

or R⁴ and R⁵, together with the atoms to which they are attached, jointo form a C₃₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one to five R¹¹;

each of R⁶, R⁷, and R⁸ is independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl,heteroaryl, —C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰R²¹, —S(O)₁₋₂R²⁰ or—S(O)₁₋₂NR²⁰, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R⁶, R⁷, and R⁸ is independentlyoptionally substituted with one to five R¹²; or two of R⁶, R⁷, and R⁸are taken together with the atoms to which they are attached to formheterocyclyl independently optionally substituted by one to three halo,oxo, or C₁₋₁₂ alkyl independently optionally substituted by one to threeoxo, halo, hydroxyl, or amino;

R⁹ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, or heterocyclyl, each of which, other than hydrogen, isoptionally substituted with one to three R¹¹;

each R¹¹ is independently halo, cyano, nitro, oxo, —OR⁶, —SR⁶, —SF₅,—NR⁶R⁷, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)R⁶, —C(O)OR⁶, —OC(O)OR⁶, —OC(O)R⁶,—C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶,—NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, or —NR⁶C(O)OR⁷, whereineach alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, andheteroaryl of R¹¹ is independently optionally substituted with one tofive R¹²;

each R¹² is independently halo, cyano, nitro, oxo, —OR³⁰, —SR³⁰, —SF₅,—NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰,—OC(O)R³⁰, —C(O)NR³⁰R³¹, —OC(O)NR³⁰R³¹, —NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰,—S(O)₁₋₂NR³⁰, —NR³⁰S(O)₁₋₂R³¹, —NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or—NR³⁰C(═O)OR³¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R² is independently optionallysubstituted with one to three halo or C₁₋₁₂ alkyl independentlyoptionally substituted by one to three oxo, halo, hydroxyl, or amino;

each R¹³ is independently halo, cyano, nitro, oxo, —OR³⁰, —SR³⁰, —SF₅,—NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰,—OC(O)R³⁰, —C(O)NR³⁰R³¹, —OC(O)NR³⁰R³¹, —NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰,—S(O)₁₋₂NR³⁰, —NR³⁰S(O)₁₋₂R³¹, —NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or—NR³⁰C(═O)OR³¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R¹³ is independently optionallysubstituted with one to three halo or C₁₋₁₂ alkyl independentlyoptionally substituted by one to three oxo, halo, hydroxyl, or amino;

each R¹⁴ is independently halo, cyano, —NR⁶R⁷, C₁₋₆ alkyl, C₁₋₆ alkoxy,or C₁₋₆ haloalkyl, or two R¹⁴ together with the atoms to which they areattached form a ring or a C═O;

each R¹⁵ is independently hydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

each R²⁰ and R²¹ is independently hydrogen or C₁₋₁₂ alkyl independentlyoptionally substituted with one to three oxo, halo, hydroxyl, or amino;or R²⁰ and R²¹ are taken together with the atoms to which they areattached to form heterocyclyl independently optionally substituted byone to three halo or C₁₋₁₂ alkyl independently optionally substituted byone to three oxo, halo, hydroxyl, or amino; and

each R³⁰ and R³¹ is independently hydrogen or C₁₋₁₂ alkyl independentlyoptionally substituted with one to three oxo, halo, hydroxyl, or amino;or R³⁰ and R³¹ are taken together with the atoms to which they areattached to form heterocyclyl independently optionally substituted byone to three halo or C₁₋₁₂ alkyl independently optionally substituted byone to three oxo, halo, hydroxyl, or amino.

In certain embodiments, when z is 0, X¹ is not O.

In certain embodiments, each R¹⁴ is independently hydrogen, halo, orC₁₋₆ alkoxy.

In certain embodiments, p is 0, 1, 2, 3, 4, or 5. In certainembodiments, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0, 1,2, or 3. In certain embodiments, p is 0, 1, or 2. In certainembodiments, p is 1. In certain embodiments, p is 0.

In certain embodiments, two R¹⁴ together with the atoms to which theyare attached form a C₃₋₆ cycloalkyl ring. In certain embodiments, twoR¹⁴ together with the atoms to which they are attached form a C₃cycloalkyl ring.

In certain embodiments, two R¹⁴ together form an ethylene bridge. Incertain embodiments, two R¹⁴ together form a methylene bridge.

In certain embodiments, provided is a compound of Formula IIA:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein z,R¹, R², R³, R⁴, R⁵, ring B, Q¹, Q², L and X¹ are as defined herein, andR²⁴ and R²⁵ are each independently hydrogen, halo, or C₁₋₆ alkoxy. Incertain embodiments, R²⁴ and R²⁵ are each independently halo. In certainembodiments, R²⁴ and R²⁵ are fluoro. In certain embodiments, R²⁴ and R²⁵are independently hydrogen or C₁₋₆ alkoxy. In certain embodiments, oneof R²⁴ and R²⁵ is hydrogen and one is methoxy.

In certain embodiments, provided is a compound of Formula IIB:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein z,R¹, R², R³, R⁴, R⁵, ring B, Q¹, Q², L and X¹ are as defined herein, andR²⁶ and R²⁷ are each independently hydrogen, halo, or C₁₋₆ alkoxy. Incertain embodiments, R²⁶ and R²⁷ are each independently halo. In certainembodiments, R²⁶ and R²⁷ are fluoro. In certain embodiments, R²⁶ and R²⁷are independently hydrogen or C₁₋₆ alkoxy. In certain embodiments, oneof R²⁶ and R²⁷ is hydrogen and one is methoxy.

In certain embodiments, provided is a compound of Formula IIC:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein z,R¹, R², R³, R⁴, R⁵, ring B, Q¹, Q², L and X¹ are as defined herein, andR²⁴ and R²⁵ are each independently hydrogen, halo, or C₁₋₆ alkoxy. Incertain embodiments, R²⁴ and R²⁵ are each independently halo. In certainembodiments, R²⁴ and R²⁵ are fluoro. In certain embodiments, R²⁴ and R²⁵are independently hydrogen or C₁₋₆ alkoxy. In certain embodiments, oneof R²⁴ and R²⁵ is hydrogen and one is methoxy.

In certain embodiments, provided is a compound of Formula IID:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein z,R¹, R², R³, R⁴, R⁵, ring B, Q¹, Q², L and X¹ are as defined herein, andR²⁶ and R²⁷ are each independently hydrogen, halo, or C₁₋₆ alkoxy. Incertain embodiments, R²⁶ and R²⁷ are each independently halo. In certainembodiments, R²⁶ and R²⁷ are fluoro. In certain embodiments, R²⁶ and R²⁷are independently hydrogen or C₁₋₆ alkoxy. In certain embodiments, oneof R²⁶ and R²⁷ is hydrogen and one is methoxy.

In certain embodiments, ring B is an optionally substituted fivemembered C₂₋₄ heteroaryl ring. In certain embodiments, ring B is a fivemembered C₂₋₄ heteroaryl ring optionally substituted with one to threeR¹³.

In certain embodiments, ring B is an optionally substituted fivemembered C₂₋₄ heteroaryl ring having 1 to 3 nitrogen ring atoms. Incertain embodiments, ring B is a five membered C₂₋₄ heteroaryl ringhaving 1 to 3 nitrogen ring atoms optionally substituted with one tothree R¹³.

In certain embodiments, ring B is an optionally substituted triazolyl,oxazolyl, imidazolyl, oxadiazolyl, or isoxazolyl. In certainembodiments, ring B is triazolyl, oxazolyl, imidazolyl, oxadiazolyl, orisoxazolyl optionally substituted with one to three R¹³.

In certain embodiments, ring B is

or optionally substituted with one to three R¹³.

In certain embodiments, ring B is a phenyl ring optionally substitutedwith one to three R¹³.

In certain embodiments, ring B is optionally substituted with one tothree R¹³, where each R¹³ is independently selected from halo, cyano,oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, or C₁₋₆ haloalkoxy.

In certain embodiments, R² is —CHF₂, —CF₃ or —CH₂CF₃.

In certain embodiments, Q¹ is O.

In certain embodiments, Q² is O.

In certain embodiments, Q¹ is NR¹⁵ and Q² is O.

In certain embodiments, Q¹ and Q² are each O.

In certain embodiments, L is a C₁₋₆ alkylene linker, optionallysubstituted with one or two methyl and optionally one to three halo. Incertain embodiments, L is a C₁₋₆ alkylene linker, optionally substitutedwith one to three halo.

In certain embodiments, L is an ethylene linker, optionally substitutedwith one or two methyl and optionally one to three halo.

In certain embodiments, L is an ethylene linker, optionally substitutedwith one to three halo.

In certain embodiments, L is —CH₂CH₂—.

In certain embodiments, the moiety -Q¹-L-Q²-R² is —OCH₂CH₂OCH₂CF₃. Incertain embodiments, the moiety -Q¹-L-Q²-R² is —OCH₂CH₂OCF₃. In certainembodiments, the moiety -Q¹-L-Q²-R² is —NR¹⁵CH₂CH₂OCF₃.

In certain embodiments, R⁴ and R⁵ are hydrogen.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, X¹ is O.

In certain embodiments, X¹ is a bond.

In certain embodiments, X¹ is O or NR⁹.

In certain embodiments, X¹ is NR⁹. In certain embodiments, R⁹ ishydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,or heterocyclyl, each of which, other than hydrogen, is optionallysubstituted with one to three halo, oxo, acetyl, amino, hydroxyl orC₁₋₁₂ alkyl.

In certain embodiments, R³ is C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which isoptionally substituted with one to five R¹¹. In certain embodiments, R³is C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is optionallysubstituted with one to three R¹¹.

In certain embodiments, R³ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, 4-15 membered heterocyclyl, C₆₋₁₀ aryl,or 5-15 membered heteroaryl, each of which, other than hydrogen, isoptionally substituted with one to five R¹¹. In certain embodiments, R³is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, 4-15 membered heterocyclyl, C₆₋₁₀ aryl, or 5-15 memberedheteroaryl, each of which, other than hydrogen, is optionallysubstituted with one to three R¹¹.

In certain embodiments, R³ is C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, orheteroaryl, each of which is optionally substituted with one to fiveR¹¹. In certain embodiments, R³ is C₃₋₁₀ cycloalkyl, heterocyclyl, aryl,or heteroaryl, each of which is optionally substituted with one to threeR¹¹.

In certain embodiments, R³ is C₃₋₁₀ cycloalkyl, 4-15 memberedheterocyclyl, aryl, or 5-15 membered heteroaryl, each of which isoptionally substituted with one to five R¹¹. In certain embodiments, R³is C₃₋₁₀ cycloalkyl, 4-15 membered heterocyclyl, aryl, or 5-15 memberedheteroaryl, each of which is optionally substituted with one to threeR¹¹.

In certain embodiments, R³ is C₃₋₁₀ cycloalkyl, aryl, or heteroaryl,each of which is optionally substituted with one to five R¹¹. In certainembodiments, R³ is C₃₋₁₀ cycloalkyl, aryl, or heteroaryl, each of whichis optionally substituted with one to three R¹¹.

In certain embodiments, R³ is aryl or heteroaryl, each of which isoptionally substituted with one to five R¹¹. In certain embodiments, R³is aryl or heteroaryl, each of which is optionally substituted with oneto three R¹¹.

In certain embodiments, R³ is aryl or heteroaryl, each of which isoptionally substituted with one to five substituents independentlyselected from halo, cyano, C₁₋₁₂ haloalkyl, and C₁₋₁₂ haloalkoxy. Incertain embodiments, R³ is aryl or heteroaryl, each of which isoptionally substituted with one to three substituents independentlyselected from halo, cyano, C₁₋₁₂ haloalkyl, and C₁₋₁₂ haloalkoxy.

In certain embodiments, R³ is aryl or heteroaryl, each of which isoptionally substituted with one to three chloro, fluoro, bromo, —CF₃, ora combination thereof. In certain embodiments, R³ is aryl or heteroaryl,each of which is optionally substituted with one to three chloro,fluoro, —CF₃, or a combination thereof.

In certain embodiments, R³ is each of which is optionally substitutedwith one to five R¹¹. In certain embodiments, R³ is,

each of which is optionally substituted with one to three R¹¹.

In certain embodiments, R³ is

each of which is optionally substituted with one to five R¹¹. In certainembodiments, R³ is

each of which is optionally substituted with one to three R¹¹.

In certain embodiments, R³ is optionally substituted phenyl. In certainembodiments, R³ is phenyl optionally substituted with one to five R¹¹.In certain embodiments, R³ is phenyl optionally substituted with one tothree R¹¹.

In certain embodiments, R³ is optionally substituted heteroaryl. Incertain embodiments, R³ is heteroaryl optionally substituted with one tofive R¹¹. In certain embodiments, R³ is heteroaryl optionallysubstituted with one to three R¹¹.

In certain embodiments, R³ is cyclobutyl, pyridinyl, triazolyl, orphenyl, each of which is optionally substituted with one to five R¹¹. Incertain embodiments, R³ is cyclobutyl, pyridinyl, triazolyl, or phenyl,each of which is optionally substituted with one to three R¹¹.

In certain embodiments, R³ is cyclobutyl, triazolyl, or phenyl, each ofwhich is optionally substituted with one to three R¹¹.

In certain embodiments, at least one R¹¹ is halo.

In certain embodiments, at least one R¹¹ is C₁₋₆ haloalkyl.

In certain embodiments, at least one R¹¹ is —CF₃.

In certain embodiments, at least one R¹¹ is —CHF₂.

In certain embodiments, at least one R¹¹ is —OCF₃.

In certain embodiments, at least one R¹¹ is —OCHF₂.

In certain embodiments, R³ is phenyl independently optionallysubstituted with one to five halo, cyano, C₁₋₁₂ alkyl optionallysubstituted with one to three halo, or C₁₋₁₂ alkoxy optionallysubstituted with one to three halo. In certain embodiments, R³ is phenylindependently optionally substituted with one to five halo, cyano, C₁₋₁₂alkyl optionally substituted with one to three halo, or C₁₋₁₂ alkoxyoptionally substituted with one to three halo.

In certain embodiments, R³ is phenyl optionally substituted with one tofive substituents independently selected from halo, cyano, C₁₋₁₂haloalkyl, and C₁₋₁₂ haloalkoxy. In certain embodiments, R³ is phenyloptionally substituted with one to three substituents independentlyselected from halo, cyano, C₁₋₁₂ haloalkyl, and C₁₋₁₂ haloalkoxy.

In certain embodiments, R³ is phenyl substituted with chloro, fluoro,bromo, —CF₃, or a combination thereof. In certain embodiments, R³ isphenyl substituted with chloro, fluoro, bromo, or a combination thereof.In certain embodiments, R³ is phenyl substituted with chloro, fluoro,—CF₃, or a combination thereof. In certain embodiments, R³ is phenylsubstituted with chloro, fluoro, or a combination thereof.

In certain embodiments, R³ is heteroaryl independently optionallysubstituted with one to five halo, cyano, C₁₋₁₂ alkyl optionallysubstituted with one to three halo, or C₁₋₁₂ alkoxy optionallysubstituted with one to three halo. In certain embodiments, R³ isheteroaryl independently optionally substituted with one to three halo.

In certain embodiments, R³ is 4-chlorophenyl, 4-chloro-3-fluorophenyl,2-((trifluoromethoxy)methyl)cyclopropyl, or3-(trifluoromethoxy)cyclobutyl.

In certain embodiments, R³ is 4-chlorophenyl, 4-fluorophenyl,4-chloro-3-fluorophenyl, 2-((trifluoromethoxy)methyl)cyclopropyl, or3-(trifluoromethoxy)cyclobutyl.

In certain embodiments, R³ is 4-chlorophenyl, 4-fluorophenyl,4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 4-methylphenyl,2-((trifluoromethoxy)methyl)cyclopropyl, or3-(trifluoromethoxy)cyclobutyl.

In certain embodiments, R³ is 4-chlorophenyl, 4-fluorophenyl,4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chloro-2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,4-methylphenyl, 2-((trifluoromethoxy)methyl)cyclopropyl,6-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)phenyl,7-bromoimidazo[1,2-a]pyridin-2-yl, 5-chlorobenzo[d]thiazol-2-yl,7-chloroisoquinolin-3-yl, 6-chlorochroman-2-yl,3-(trifluoromethoxy)pyrrolidin-1-yl, or 3-(trifluoromethoxy)cyclobutyl.

In certain embodiments, R³ is 4-chlorophenyl, 4-fluorophenyl,4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,4-chloro-2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,4-methylphenyl, 2-((trifluoromethoxy)methyl)cyclopropyl,6-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)phenyl,7-bromoimidazo[1,2-a]pyridin-2-yl, 5-chlorobenzo[d]thiazol-2-yl,7-chloroisoquinolin-3-yl, 6-chloroquinolin-2-yl,6-fluoroisoquinolin-2-yl, 6-(trifluoromethyl)quinolin-2-yl,6-chlorochroman-2-yl, 6-fluorochroman-2-yl, 6,7-difluoroquinolin-2-yl,5,6-difluoroquinolin-2-yl, 3-(trifluoromethoxy)pyrrolidin-1-yl, or3-(trifluoromethoxy)cyclobutyl.

In certain embodiments, R³ is 4-chlorophenyl, 4-bromophenyl,3-fluoro-4-(trifluoromethyl)phenyl, 6-(trifluoromethyl)quinazolin-2-yl,6-(trifluoromethyl)quinolin-2-yl, 6-(trifluoromethyl)quinoxalin-2-yl,6-chloro-7-fluoro-quinoxalin-2-yl,6-fluoro-7-(trifluoromethyl)quinoxalin-2-yl,7-fluoro-6-(trifluoromethyl)quinoxalin-2-yl,7-fluoro-6-(trifluoromethyl)quinolin-2-yl, or6-chloro-7-fluoro-quinolin-2-yl.

In certain embodiments, z is 0. In certain embodiments, z is 1.

In certain embodiments, z is 0, X¹ is a bond, and R is optionallysubstituted heteroaryl. In certain embodiments, z is 0, X¹ is a bond,and R is heteroaryl optionally substituted with one to three R¹¹.

In certain embodiments, R⁴ and R⁵ are independently hydrogen, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl or C₂₋₁₂ alkynyl, each of which, other thanhydrogen, is independently optionally substituted with one to three(e.g., one to three) halo, oxo, acetyl, amino, or hydroxyl.

In certain embodiments, R⁴ and R⁵ are hydrogen.

In certain embodiments, provided is a compound of Formula IIIA:

wherein each of R², R³, ring A, ring B, Q¹, Q², L and X¹ are as definedherein.

In certain embodiments, provided is a compound of Formula IIIB:

wherein each of R², R³, R¹⁴, p, ring B, Q¹, Q², L and X¹ are as definedherein.

In certain embodiments, provided is a compound of Formula IIIC:

wherein each of R², R¹¹, m, ring A, ring B, Q¹, Q², and L are as definedherein.

In certain embodiments, provided is a compound of Formula IIID:

wherein each of R², R¹¹, m, R¹⁴, p, ring B, Q¹, Q², and L are as definedherein.

In certain embodiments, provided is a compound of Formula IIIE:

wherein each of R², R³, ring A, ring B, Q¹, Q², and L are as definedherein.

In certain embodiments, provided is a compound of Formula IIIF:

wherein each of R², R³, R¹⁴, p, ring B, Q¹, Q², and L are as definedherein.

In certain embodiments, provided is a compound selected from Table 1:

TABLE 1 Ex. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

23

24

25

26

27

28

29

30

31

32

33

or a pharmaceutically acceptable salt, isotopically enriched analog,prodrug, stereoisomer, or a mixture of stereoisomers thereof.

In certain embodiments, provided is a compound selected from Table 2.

TABLE 2 Structure

or a pharmaceutically acceptable salt, isotopically enriched analog,prodrug, stereoisomer, or a mixture of stereoisomers thereof.

In certain embodiments, provided is a compound selected from Table 1A:

TABLE 1A Ex. Structure 21

22

or a pharmaceutically acceptable salt, isotopically enriched analog,prodrug, stereoisomer, or a mixture of stereoisomers thereof.

In certain embodiments, provided is a compound selected from Table 2A:

TABLE 2A Structure

or a pharmaceutically acceptable salt, isotopically enriched analog,prodrug, stereoisomer, or a mixture of stereoisomers thereof.

3. Methods

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapy,and/or veterinary applications. In some embodiments, the subject is amammal. In certain embodiments, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition of as described herein. Thetherapeutically effective amount may vary depending on the subject, anddisease or condition being treated, the weight and age of the subject,the severity of the disease or condition, and the manner ofadministering, which can readily be determined by one of ordinary skillin the art.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. In this context, the compoundsand compositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of acompound of the present disclosure for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the compounds andcompositions described herein may be suited are described below or willbecome apparent to those skilled in the art. The selected compounds maybe further characterized to examine the safety or tolerance dosage inhuman or non-human subjects. Such properties may be examined usingcommonly known methods to those skilled in the art.

In certain embodiments, the compounds disclosed herein can be used totreat cellular proliferative disorders, including both cancerous andnon-cancerous cellular proliferative disorders. Treatment of cellularproliferative disorders may comprise, but is not limited to, inhibitingcellular proliferation, including rapid proliferation. It iscontemplated that the compounds described herein can be used to treatany type of cancer, including, but not limited to, carcinomas, sarcomas,lymphomas, leukemias, and germ cell tumors. Exemplary cancers include,but are not limited to, adrenocortical carcinoma, anal cancer, appendixcancer, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bonecancer, osteosarcoma or malignant fibrous histiocytoma, brain cancer(e.g., brain stem glioma, astrocytoma (e.g., cerebellar, cerebral,etc.), atypical teratoid/rhabdoid tumor, central nervous systemembryonal tumors, malignant glioma, craniopharyngioma, ependymoblastoma,ependymoma, medulloblastoma, medulloepithelioma, pineal parenchymaltumors of intermediate differentiation, supratentorial primitiveneuroectodermal tumors and/or pineoblastoma, visual pathway and/orhypothalamic glioma, brain and spinal cord tumors, etc.), breast cancer,bronchial tumors, carcinoid tumor (e.g., gastrointestinal, etc.),carcinoma of unknown primary, cervical cancer, chordoma, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, embryonaltumors, cancers of the central nervous system, endometrial cancer,ependymoma, esophageal cancer, Ewing family of tumors, eye cancer (e.g.,intraocular melanoma, retinoblastoma, etc.), gallbladder cancer, gastriccancer, gastrointestinal tumor (e.g., carcinoid tumor, stromal tumor(gist), stromal cell tumor, etc.), germ cell tumor (e.g., extracranial,extragonadal, ovarian, etc.), gestational trophoblastic tumor, head andneck cancer, hepatocellular cancer, hypopharyngeal cancer, hypothalamicand visual pathway glioma, intraocular melanoma, islet cell tumors,Kaposi sarcoma, kidney cancer, large cell tumors, laryngeal cancer(e.g., acute lymphoblastic, acute myeloid, etc.), leukemia (e.g.,myeloid, acute myeloid, acute lymphoblastic, chronic lymphocytic,chronic myelogenous, multiple myelogenous, hairy cell, etc.), lip and/ororal cavity cancer, liver cancer, lung cancer (e.g., non-small cell,small cell, etc.), lymphoma (e.g., AIDS-related, Burkitt, cutaneousTcell, Hodgkin, non-Hodgkin, primary central nervous system, cutaneousT-cell, Waldenström macroglobulinemia, etc.), malignant fibroushistiocytoma of bone and/or osteosarcoma, medulloblastoma,medulloepithelioma, merkel cell carcinoma, mesothelioma, metastaticsquamous neck cancer, mouth cancer, multiple endocrine neoplasiasyndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases(e.g., myeloproliferative disorders, chronic, etc.), nasal cavity and/orparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oralcancer; oral cavity cancer, oropharyngeal cancer; osteosarcoma and/ormalignant fibrous histiocytoma of bone; ovarian cancer (e.g., ovarianepithelial cancer, ovarian germ cell tumor, ovarian low malignantpotential tumor, etc.), pancreatic cancer (e.g., islet cell tumors,etc.), papillomatosis, paranasal sinus and/or nasal cavity cancer,parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma,pineal parenchymal tumors of intermediate differentiation, pineoblastomaand supratentorial primitive neuroectodermal tumors, pituitary tumor,plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma,prostate cancer, rectal cancer, renal cell cancer, transitional cellcancer, respiratory tract carcinoma involving the nut gene on chromosome15, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma(e.g., Ewing family of tumors, Kaposi, soft tissue, uterine, etc.),Sézary syndrome, skin cancer (e.g., non-melanoma, melanoma, merkel cell,etc.), small intestine cancer, squamous cell carcinoma, squamous neckcancer with occult primary, metastatic, stomach cancer, supratentorialprimitive neuroectodermal tumors, testicular cancer, throat cancer,thymoma and/or thymic carcinoma, thyroid cancer, transitional cellcancer of the renal, pelvis and/or ureter (e.g., trophoblastic tumor,unknown primary site carcinoma, urethral cancer, uterine cancer,endometrial, uterine sarcoma, etc.), vaginal cancer, visual pathwayand/or hypothalamic glioma, vulvar cancer, Wilms tumor, and the like.Examples of noncancerous cellular proliferative disorders include, butare not limited to, fibroadenoma, adenoma, intraductal papilloma, nippleadenoma, adenosis, fibrocystic disease or changes of breast, plasma cellproliferative disorder (PCPD), restenosis, atherosclerosis, rheumatoidarthritis, myofibromatosis, fibrous hamartoma, granular lymphocyteproliferative disorders, benign hyperplasia of prostate, heavy chaindiseases (HCDs), lymphoproliferative disorders, psoriasis, idiopathicpulmonary fibrosis, scleroderma, cirrhosis of the liver, IgAnephropathy, mesangial proliferative glomerulonephritis,membranoproliferative glomerulonephritis, hemangiomas, vascular andnon-vascular intraocular proliferative disorders, and the like.

In certain embodiments, the compounds disclosed herein can be used totreat lung injury and/or lung inflammation.

In certain embodiments, the compounds disclosed herein can be used totreat cancer, pre-cancerous syndromes and diseases/injuries associatedwith activated unfolded protein response pathways, such as Alzheimer'sdisease, neuropathic pain, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, Parkinson's disease, diabetes, metabolicsyndrome, metabolic disorders, Huntington's disease, Creutzfeldt-JakobDisease, fatal familial insomnia, Gerstmann-Straussler-Scheinkersyndrome, and related prion diseases, amyotrophic lateral sclerosis,progressive supranuclear palsy, myocardial infarction, cardiovasculardisease, inflammation, organ fibrosis, chronic and acute diseases of theliver, fatty liver disease, liver steatosis, liver fibrosis, chronic andacute diseases of the lung, lung fibrosis, chronic and acute diseases ofthe kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE),neurodegeneration, dementias, frontotemporal dementias, tauopathies,Pick's disease, Neimann-Pick's disease, amyloidosis, cognitiveimpairment, atherosclerosis, ocular diseases, arrhythmias, in organtransplantation and in the transportation of organs for transplantation.

In embodiments, the compounds disclosed herein can be used to treat orlessen the severity of cancer, Alzheimer's disease, stroke, Type 1diabetes, Parkinson disease, Huntington's disease, amyotrophic lateralsclerosis, myocardial infarction, cardiovascular disease,atherosclerosis, arrhythmias, or age-related macular degeneration.

In certain embodiments, the compounds disclosed herein can be used totreat neuropathic pain.

In certain embodiments, the compounds disclosed herein can be used totreat or lessen the severity of ocular diseases/angiogenesis. In certainembodiments, the ocular disease includes vascular leakage (e.g., edemaor neovascularization for any occlusive or inflammatory retinal vasculardisease, such as rubeosis irides, neovascular glaucoma, pterygium,vascularized glaucoma filtering blebs, conjunctival papilloma),choroidal neovascularization (e.g., neovascular age-related maculardegeneration (AMD), myopia, prior uveitis, trauma, or idiopathic),macular edema (e.g., post surgical macular edema, macular edemasecondary to uveitis including retinal and/or choroidal inflammation,macular edema secondary to diabetes, and macular edema secondary toretinovascular occlusive disease (i.e. branch and central retinal veinocclusion)), retinal neovascularization due to diabetes (e.g., retinalvein occlusion, uveitis, ocular ischemic syndrome from carotid arterydisease, ophthalmic or retinal artery occlusion, sickle cellretinopathy, other ischemic or occlusive neovascular retinopathies,retinopathy of prematurity, or Eale's Disease), and genetic disorders(e.g., VonHippel-Lindau syndrome). In certain embodiments, theneovascular age-related macular degeneration is wet age-related maculardegeneration. In certain embodiments, the neovascular age-relatedmacular degeneration is dry age-related macular degeneration and thepatient is characterized as being at increased risk of developing wetage-related macular degeneration.

In certain embodiments, the compounds disclosed herein can be used totreat viral infections (e.g., to prevent the initiation of viral proteinsynthesis). Exemplary viruses which can be treated using the compoundsdisclosed herein include, but are not limited to, picornaviridae (e.g.,polioviruses), reoviridae (e.g., rotaviruses), togaviridae (e.g.,encephalitis viruses, yellow fever virus, rubella virus, etc.),orthomyxoviridae (e.g., influenza viruses), paramyxoviridae (e.g.,respiratory syncytial virus, measles virus, mumps virus, parainfluenzavirus, etc.), rhabdoviridae (e.g., rabies virus), coronaviridae,bunyaviridae, flaviviridae, filoviridae, arenaviridae, bunyaviridae, andretroviridae (e.g., human T-cell lymphotropic viruses (HTLV), humanimmunodeficiency viruses (HIV), etc.), papovaviridae (e.g., papillomaviruses), adenoviridae (e.g., adenovirus), herpesviridae (e.g., herpessimplex viruses), and poxyiridae (e.g., variola viruses). In certainembodiments, the viral infection is caused by hepatitis B virus,hepatitis C virus, and/or HIV.

In certain embodiments, the compounds disclosed herein can be used totreat disorders associated with viral infections. Such disordersinclude, but are not limited to neurological symptoms (e.g.,encephalitis, meningoencephalitis, paralysis, myelopathy, neuropathy,aseptic meningitis, hemiparesis, dementia, dysphagia, lack of muscularcoordination, impaired vision, coma, etc.), wasting symptoms (e.g.,inflammatory cell infiltration, perivascular cuffing of blood vessels,demyelination, necrosis, reactive gliosis, etc.), gastroenteritissymptoms (e.g., diarrhea, vomiting, cramps, etc.), hepatitis symptoms(nausea, vomiting, right upper quadrant pain, raised liver enzyme levels(e.g., AST, ALT, etc.), jaundice, etc.), hemorrhagic fever symptoms(e.g., headache, fever, chills body pains, diarrhea, vomiting,dizziness, confusion, abnormal behavior, pharyngitis, conjunctivitis,red face, red neck, hemorrhage, organ failure, etc.), oncogenic symptoms(e.g., sarcomas, leukemias, and the like, as well as “rare”malignancies, e.g., Kaposi's sarcoma, oral hairy leukoplasia, lymphomas,etc.), immunodeficiency symptoms (e.g., opportunistic infections,wasting, rare malignancies, neurological disease, fever, diarrhea, skinrashes, etc.), lesions (e.g., warts (e.g., common wart, flat wart, deephyperkeratotic palmoplantar wart, superficial mosaic type palmoplantarwart, etc.)), epidermodysplasia, mucosal lesions, ulcers, and systemicsymptoms (e.g., fever, chills, headache, muscle pain, bone pain, jointpain, pharyngitis, tonsillitis, sinusitis, otitis, bronchitis,pneumonia, bronchopneumonia, nausea, vomiting, increased salivation,rash, macules, lymphadenopathy, arthritis, ulcers, photosensitivity,weight loss, irritability, restlessness, anxiety, coma, death, etc.).

In certain embodiments, the compounds disclosed herein can be used totreat disorders characterized by unwanted synthesis and/or abnormalaccumulation of one or more mutant and/or wild-type proteins. It iscontemplated that the compounds disclosed herein that can inhibittranslation initiation and thus can reduce the load on theprotein-folding machinery and, accordingly, may reduce the severity ofthe disorder. Disorders associated with unwanted synthesis and/orabnormal accumulation of one or more mutant and/or wild-type proteinsinclude, but are not limited to, Tay-Sachs disease, cystic fibrosis,phenylketonuria, Fabry disease, Alzheimer's disease, Huntington'sdisease, Parkinson's disease, frontotemporal dementia, congophilicangiopathy, prion related disorders (i.e., transmissible spongiformencephalopathies such as Creutzfeldt-Jacob disease, kuru, fatal familialinsomnia, scrapie, bovine spongiform encephalopathy, etc.), and thelike.

It is contemplated that the compounds and compositions disclosed hereinare capable of inhibiting neuronal cell death, such as in prion disease.Generally, the method includes administering a therapeutically effectiveamount of a compound or composition as described herein, to a patient inneed thereof.

In some embodiments, the disorder is a neurodegenerative disease. Theterm “neurodegenerative disease” refers to a disease or condition inwhich the function of a subject's nervous system becomes impaired.Examples of neurodegenerative diseases include, e.g., Alexander'sdisease, Alper's disease, Alzheimer's disease, amyotrophic lateralsclerosis, ataxia telangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiformencephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasaldegeneration, Creutzfeldt-Jakob disease, frontotemporal dementia,Gerstmann-Straussler-Scheinker syndrome, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewybody dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3),Multiple sclerosis, Multiple System Atrophy, narcolepsy,Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease,Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum'sdisease, Sandhoffs disease, Schilder's disease, Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia,Schizophrenia, Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, vanishing white matter (VWM) disease, insulin resistance orTabes dorsalis.

Other embodiments include use of the presently disclosed compounds intherapy. Some embodiments include their use in the treatment of aneurodegenerative disease.

In other embodiments, provided are the presently disclosed compounds foruse in the treatment of Alzheimer's disease, Parkinson's disease,dementia, or ALS.

In other embodiments, provided is the use of the presently disclosedcompounds or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for treating a neurodegenerative disease.

In other embodiments, provided is the use of the presently disclosedcompounds or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for treating Alzheimer's disease,Parkinson's disease, dementia, or ALS.

In other embodiments, provided is the use of the presently disclosedcompounds, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for treating cancer.

In other embodiments, provided is the presently disclosed compounds, orpharmaceutically acceptable salt thereof, for use in therapy.

In other embodiments, provided is the presently disclosed compounds, orpharmaceutically acceptable salt thereof, for use in treating aneurodegenerative disease.

In other embodiments, provided is the presently disclosed compounds, orpharmaceutically acceptable salt thereof, for use in treating cancer.

4. Kits

Provided herein are also kits that include a compound of the disclosure,or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitablepackaging. In certain embodiments, a kit further includes instructionsfor use. In one aspect, a kit includes a compound of the disclosure, ora pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, and a labeland/or instructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof in a suitable container. The container may be a vial, jar,ampoule, preloaded syringe, or intravenous bag.

5. Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that contain one or more of the compoundsdescribed herein a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or prodrug thereof, and one or morepharmaceutically acceptable vehicles selected from carriers, adjuvants,and excipients. Suitable pharmaceutically acceptable vehicles mayinclude, for example, inert solid diluents and fillers, diluents,including sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers, and adjuvants. Such compositions areprepared in a manner well known in the pharmaceutical art. See, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal, andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, the activeingredient is usually diluted by an excipient and/or enclosed withinsuch a carrier that can be in the form of a capsule, sachet, paper orother container. When the excipient serves as a diluent, it can be inthe form of a solid, semi-solid, or liquid material, which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include, e.g., lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl and propylhydroxy-benzoates; sweetening agents; and flavoringagents.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof can beformulated so as to provide quick, sustained or delayed release of theactive ingredient after administration to the subject by employingprocedures known in the art. Controlled release drug delivery systemsfor oral administration include osmotic pump systems and dissolutionalsystems containing polymer-coated reservoirs or drug-polymer matrixformulations. Another formulation for use in the methods disclosedherein employ transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds described herein in controlled amounts. The constructionand use of transdermal patches for the delivery of pharmaceutical agentsis well known in the art. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof. When referring to these preformulation compositions ashomogeneous, the active ingredient may be dispersed evenly throughoutthe composition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills, andcapsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedherein. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

6. Dosing

The specific dose level of a compound of the present application for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. In some embodiments, a dosage of from about 0.0001 to about100 mg per kg of body weight per day, from about 0.001 to about 50 mg ofcompound per kg of body weight, or from about 0.01 to about 10 mg ofcompound per kg of body weight may be appropriate. Normalizing accordingto the subject's body weight is particularly useful when adjustingdosages between subjects of widely disparate size, such as occurs whenusing the drug in both children and adult humans or when converting aneffective dosage in a non-human subject such as dog to a dosage suitablefor a human subject.

7. Synthesis of the Compounds

The compounds may be prepared using the methods disclosed herein androutine modifications thereof, which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein may beaccomplished as described in the following examples. If available,reagents and starting materials may be purchased commercially, e.g.,from Sigma Aldrich or other chemical suppliers.

It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, conventional protecting groups (“PG”) may be necessary toprevent certain functional groups from undergoing undesired reactions.Suitable protecting groups for various functional groups as well assuitable conditions for protecting and deprotecting particularfunctional groups are well known in the art. For example, numerousprotecting groups are described in Wuts, P. G. M., Greene, T. W., &Greene, T. W. (2006). Greene's protective groups in organic synthesis.Hoboken, N.J., Wiley-Interscience, and references cited therein. Forexample, protecting groups for alcohols, such as hydroxyl, include silylethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS)ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF(tetra-n-butylammonium fluoride), HF-Py, or HF-NEt₃. Other protectinggroups for alcohols include acetyl, removed by acid or base, benzoyl,removed by acid or base, benzyl, removed by hydrogenation,methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed byacid, methoxymethyl ether, removed by acid, tetrahydropyranyl ortetrahydrofuranyl, removed by acid, and trityl, removed by acid.Examples of protecting groups for amines include carbobenzyloxy, removedby hydrogenolysis p-methoxybenzyl carbonyl, removed by hydrogenolysis,tert-butyloxycarbonyl, removed by concentrated strong acid (such as HClor CF₃COOH), or by heating to greater than about 80° C.,9-fluorenylmethyloxycarbonyl, removed by base, such as piperidine,acetyl, removed by treatment with a base, benzoyl, removed by treatmentwith a base, benzyl, removed by hydrogenolysis, carbamate group, removedby acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis,3,4-dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removedby ammonium cenum(IV) nitrate, tosyl, removed by concentrated acid (suchas HBr or H₂SO₄) and strong reducing agents (sodium in liquid ammonia orsodium naphthalenide), troc (trichloroethyl chloroformate), removed byZn insertion in the presence of acetic acid, and sulfonamides (Nosyl &Nps), removed by samarium iodide or tributyltin hydride.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

General Synthesis

The following reaction shown in Scheme I illustrates a general methodwhich can be employed for the synthesis of compounds disclosed herein.In Scheme I, z, R¹, R², R³, R⁴, R⁵, ring A, ring B, Q¹, Q², L and X¹ areas defined herein, R¹⁰⁰ is halo, R¹⁰¹ is the moiety

or a nitrogen protecting group, R¹⁰² is C₁₋₆ alkyl, and LG is leavinggroup (e.g., C₁₋₆ alkoxy or halo). The coupling of compound of Formula 1with the compound of Formula H-Q¹-L-Q²-R² provide a compound of Formula2, can be performed under standard coupling conditions (e.g.,nucleophilc aromatic substitution reaction conditions). When R¹⁰¹ is themoiety

the resulting compound is of Formula I. When R¹⁰¹ is a nitrogenprotecting group, the method further comprises deprotecting the nitrogenatom and contacting the resulting intermediate with a compound ofFormula 3, thus providing a compound of Formula I.

Accordingly, in certain embodiments, provided is a method of preparing acompound of Formula I, comprising coupling a compound of Formula 1:

comprising contacting a compound of Formula 1:

wherein R¹⁰⁰ is halo and R¹⁰¹ is the moiety

or a nitrogen protecting group; with a compound of Formula H-Q¹-L-Q²-R²,under conditions suitable to provide a compound of Formula 2:

wherein:

a) when R¹⁰¹ is the moiety

the method provides the compound of Formula I, or a salt, isotopicallyenriched analog, stereoisomer, or mixture of stereoisomers thereof, and

b) when R¹⁰¹ is a nitrogen protecting group, the method furthercomprises removing the nitrogen protecting group and contacting thecompound of Formula 2 with a compound of Formula 3:

under conditions suitable to provide the compound of Formula I, or asalt, isotopically enriched analog, stereoisomer, or mixture ofstereoisomers thereof, wherein z, R¹, R², R³, R⁴, R⁵, ring A, ring B,Q¹, Q², L and X¹ are as defined herein, and LG is leaving group (e.g.,—OH, C₁₋₆ alkoxy or halo).

The coupling of the compound of Formula 2 with the compound of Formula 3typically employs a suitable reagent, such as a carbodiimide (e.g.,N,N′-dicyclohexylcarbodiimide (DCC), N,N′-dicyclopentylcarbodiimide,N,N′-diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),N-t-butyl-N-methylcarbodiimide (BMC), N-t-butyl-N-ethylcarbodiimide(BEC), 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC),etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides), anactivated ester (e.g., phenyl activated ester derivatives, p-hydroxamicactivated ester, hexafluoroacetone (HFA), etc.), acylazoles(acylimidazoles using CDI, acylbenzotriazoles, etc.), acyl azides, acidhalides, phosphonium salts (HOBt, PyBOP, HOAt, etc.), aminium/uroniumsalts (e.g., tetramethyl aminium salts, bispyrrolidino aminium salts,bispiperidino aminium salts, imidazolium uronium salts, pyrimidiniumuronium salts, uronium salts derived fromN,N,N′-trimethyl-N′-phenylurea, morpholino-based aminium/uroniumcoupling reagents, antimoniate uronium salts, etc.), an organophosphorusreagent (e.g., phosphinic and phosphoric acid derivatives, such aspropylphosphonic anhydride), organosulfur reagents (e.g., sulfonic acidderivatives), a triazine coupling reagent (e.g.,2-chloro-4,6-dimethoxy-1,3,5-triazine,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholiniumtetrafluoroborate, etc.), pyridinium coupling reagents (e.g.,Mukaiyama's reagent, pyridinium tetrafluoroborate coupling reagents,etc.), and the like (see, e.g., El-Faham, et al. Chem. Rev., 2011,111(11): 6557-6602; Han, et al. Tetrahedron, 2004, 60:2447-2467).

The following reaction shown in Scheme II illustrates exemplary generalmethods which can be employed for the synthesis of various B ringsdescribed herein, which methods can be utilized to prepare variouscompounds of Formula 1, which can be used in the methods describedherein, e.g., Scheme I, to provide compounds of Formula I. In Scheme II,R¹ and ring A are as defined herein and R¹⁰¹ is the moiety

or a nitrogen protecting group. In Scheme II, compounds of Formula Iwhere ring B is isoxazolyl can be prepared from the corresponding alkyneas in compounds of Formula 1-a. Compounds of Formula I where ring B isoxadiazolyl can be prepared from the corresponding ester (e.g., methylester) as in compounds of Formula 1-b. Compounds of Formula I where ringB is oxadiazolyl can be prepared from the correspondinghydrazinecarbonyl as in compounds of Formula 1-c, via the correspondingester (e.g., methyl ester) as in compounds of Formula 1-b. Compounds ofFormula I where ring B is oxadiazolyl can be prepared from thecorresponding cyano-substituted intermediate as in compounds of Formula1-d. Compounds of Formula I where ring B is oxazolyl can be preparedfrom the corresponding alpha-halo ester as in compounds of Formula 1-e.Alternatively, compounds of Formula I where ring B is isoxazolyl can beprepared from the corresponding methyl oxopropanoate as in compounds ofFormula 1-f.

Appropriate starting materials and reagents (i.e., diamines, esters, andacids) can be purchased or prepared by methods known to one of skill inthe art.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

General Experimental Methods

All solvents used were commercially available and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of nitrogen.

NMR Spectroscopy: ¹H Nuclear magnetic resonance (NMR) spectroscopy wascarried out using a Bruker Avance III equipped with a BBFO 300 MHz probeoperating at 300 MHz or one of the following instruments: a BrukerAvance 400 instrument equipped with probe DUAL 400 MHz S1, a BrukerAvance 400 instrument equipped with probe 6 S1 400 MHz 5 mm ¹H-¹³C ID, aBruker Avance III 400 instrument with nanobay equipped with probeBroadband BBFO 5 mm direct, a Bruker Mercury Plus 400 NMR spectrometerequipped with a Bruker 400 BBO probe with all operating at 400 MHz. Alldeuterated solvents contained typically 0.03% to 0.05% v/vtetramethylsilane, which was used as the reference signal (set at δ 0.00for both ¹H and ¹³C). In certain cases, ¹H Nuclear magnetic resonance(NMR) spectroscopy was carried out using a Bruker Advance 400 instrumentoperating at 400 MHz using the stated solvent at around room temperatureunless otherwise stated. In all cases, NMR data were consistent with theproposed structures. Characteristic chemical shifts (δ) are given inparts-per-million using conventional abbreviations for designation ofmajor peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd,doublet of doublets; dt, doublet of triplets; br, broad.

Thin Layer Chromatography: Where thin layer chromatography (TLC) hasbeen used it refers to silica gel TLC using silica gel F254 (Merck)plates, Rf is the distance travelled by the compound divided by thedistance travelled by the solvent on a TLC plate. Column chromatographywas performed using an automatic flash chromatography system over silicagel cartridges or in the case of reverse phase chromatography over C18cartridges. Alternatively, thin layer chromatography (TLC) was performedon Alugram® (Silica gel 60 F254) from Mancherey-Nagel and UV wastypically used to visualize the spots. Additional visualization methodswere also employed in some cases. In these cases the TLC plate wasdeveloped with iodine (generated by adding approximately 1 g of I₂ to 10g silica gel and thoroughly mixing), ninhydrin (available commerciallyfrom Aldrich), or Magic Stain (generated by thoroughly mixing 25 g(NH₄)₆Mo₇O₂₄.4H₂O, 5 g (NH₄)₂Ce(IV)(NO₃)₆ in 450 mL water and 50 mLconcentrated H₂SO₄) to visualize the compound.

Liquid Chromatography-Mass Spectrometry and HPLC Analysis: HPLC analysiswas performed on Shimadzu 20AB HPLC system with a photodiode arraydetector and Luna-C18(2) 2.0×50 mm, 5 μm column at a flow rate of 1.2mL/min with a gradient solvent Mobile phase A (MPA, H₂O+0.037% (v/v)TFA): Mobile phase B (MPB, ACN+0.018% (v/v) TFA) (0.01 min, 10% MPB; 4min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB).LCMS was detected under 220 and 254 nm or used evaporative lightscattering (ELSD) detection as well as positive electrospray ionization(MS). Semi-preparative HPLC was performed by either acidic or neutralconditions. Acidic: Luna C18 100×30 mm, 5 m; MPA: HCl/H₂O=0.04%, orformic acid/H₂O=0.2% (v/v); MPB: ACN. Neutral: Waters Xbridge 150×25, 5m; MPA: 10 mM NH₄HCO₃ in H₂O; MPB: ACN. Gradient for both conditions:10% of MPB to 80% of MPB within 12 min at a flow rate of 20 mL/min, then100% MPB over 2 min, 10% MPB over 2 min, UV detector. SFC analysis wasperformed on Thar analytical SFC system with a UV/Vis detector andseries of chiral columns including AD-3, AS-H, OJ-3, OD-3, AY-3 andIC-3, 4.6×100 mm, 3 μm column at a flow rate of 4 mL/min with a gradientsolvent Mobile phase A (MPA, CO₂): Mobile phase B (MPB, MeOH+0.05% (v/v)IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min,10% MPB). SFC preparative was performed on Thar 80 preparative SFCsystem with a UV/Vis detector and series of chiral preparative columnsincluding AD-H, AS-H, OJ-H, OD-H, AY-H and IC-H, 30×250 mm, 5 um columnat a flow rate of 65 mL/min with a gradient solvent Mobile phase A (MPA,CO₂): Mobile phase B (MPB, MeOH+0.1% (v/v) NH₃H₂O) (0.01 min, 10% MPB; 5min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10% MPB). LC-MS data were alsocollected using an UPLC-MS Acquity™ system equipped with PDA detectorand coupled to a Waters single quadrupole mass spectrometer operating inalternated positive and negative electrospray ionization mode. Thecolumn used was a Cortecs UPLC C18, 1.6 μm, 2.1×50 mm. A linear gradientwas applied, starting at 95% A (A: 0.1% formic acid in water) and endingat 95% B (B: 0.1% formic acid in MeCN) over 2.0 min with a total runtime of 2.5 min. The column temperature was at 40° C. with the flow rateof 0.8 mL/min.

General procedure A, T3P coupling: To a flask containing amine (1 eq),and carboxylic acid (1.5 eq) in DMF or EtOAc (0.1 M-0.2 M) were addedeither N-methylimidazole, diisopropylethylamine, or triethylamine(3.0-5.0 eq) followed by T3P solution (1.5-3.0 eq., 50% in EtOAc). Theresulting reaction mixture was stirred at rt for 4 h, at which point 1MNaOH solution was added followed by EtOAc. The layers were separated,and the aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. The crude reaction mixture waspurified employing silica flash chromatography or reverse-phase HPLC toprovide the desired product.

General procedure B, Hydrazide Formation: To a suspension of the methylester (1 eq) in EtOH (0.25-0.1M) was added hydrazine hydrate (3-5 eq)and the reaction mixture was heated at 90° C. overnight. The reactionmixture was cooled to rt often causing the product to crystallize out ofsolution. This solid was collected by removal of the supernatant. If theproduct did not crystallize, the solution was concentrated, and thecrude product was sufficiently pure to use in subsequent steps.

Intermediate 1: tert-butyl((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate

tert-butyl((3R,6S)-6-(5-mercapto-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a mixture of tert-butyl((3R,6S)-6-(hydrazinecarbonyl)tetrahydro-2H-pyran-3-yl)carbamate (1.0 g,3.86 mmol) in MeOH (15 mL) was added KOH (260 mg, 4.63 mmol), themixture was stirred at 25° C. for 0.5 h, CS₂ (587 mg, 7.71 mmol) wasadded and the mixture was stirred at 80° C. for 16 h. The reactionmixture was concentrated under reduced pressure to give a residue andthe residue was redissolved with H₂O (50 mL), and then adjusted pH=3,filtered and the filtered cake was concentrated under reduced pressureto give the desired product. LCMS: m/z=246.1 [M−55]⁺. ¹H NMR (400 MHz,CDCl₃) δ=4.58-4.41 (m, 2H), 4.15 (br d, J=7.8 Hz, 1H), 3.76 (br d,J=18.3 Hz, 1H), 3.25 (brt, J=10.1 Hz, 1H), 2.27-1.95 (m, 3H), 1.46 (brs, 10H).

tert-butyl((3R,6S)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a mixture of tert-butyl((3R,6S)-6-(5-mercapto-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(3.7 g, 12.28 mmol) in DMF (60 mL) was added K₂CO₃ (3.39 g, 24.56 mmol)and Mel (3.49 g, 24.56 mmol), and the mixture was stirred at 20° C. for12 h. The reaction mixture was diluted with H₂O (50 mL), and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by silica gelcolumn chromatography (PE:EtOAc=1:0 to 0:1) to afford the desiredproduct. LCMS: m/z=260.1 [M−55]⁺. ¹H NMR (400 MHz, CDCl₃) δ=4.62 (br dd,J=2.8, 9.5 Hz, 1H), 4.49 (br s, 1H), 4.14 (br dd, J=3.4, 10.9 Hz, 1H),3.81-3.69 (m, 1H), 3.26 (brt, J=10.0 Hz, 1H), 2.72 (s, 3H), 2.27-2.00(m, 3H), 1.56-1.39 (m, 10H).

tert-butyl((3R,6S)-6-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a mixture of tert-butyl((3R,6S)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(2.6 g, 8.24 mmol) in DCM (40 mL) was added m-CPBA (7.11 g, 32.98 mmol,80% purity) at 25° C. under N₂, and the mixture was stirred at 25° C.for 16 h. The reaction mixture was diluted with Na₂S2O₃ solution (3×40mL), was washed with NaHCO₃ solution (3×40 mL), and extracted with DCM(3×30 mL). The combined organic layers were washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give the desired product. LCMS: m/z=292.0 [M−55]⁺. ¹H NMR(400 MHz, CDCl₃) δ=4.74 (dd, J=2.8, 10.2 Hz, 1H), 4.46 (br s, 1H), 4.19(br dd, J=3.6, 10.7 Hz, 1H), 3.77 (br d, J=6.2 Hz, 1H), 3.48 (s, 3H),3.29 (brt, J=10.0 Hz, 1H), 2.31-2.05 (m, 3H), 1.63-1.38 (m, 10H).

tert-butyl((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a solution of 2-(trifluoromethoxy)ethanol (7.49 g, 2.88 mmol, 5%solution in THF) was added NaH (138 mg, 3.45 mmol, 60% in mineral oil),and the mixture was stirred at 0° C. for 0.5 h under N₂. Then tert-butyl((3R,6S)-6-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(1.0 g, 2.88 mmol) was added, and the mixture was stirred at 25° C. for2 h. The reaction mixture was diluted with NH₄Cl (20 mL), and extractedwith EtOAc (3×20 mL). The combined organic layers were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by silica gelcolumn chromatography (PE:EtOAc=1:0 to 1:1) to deliver the desiredproduct. LCMS: m/z=342.1 [M−55]⁺. ¹H NMR (400 MHz, CDCl₃) δ=4.73-4.67(m, 2H), 4.51 (m, 2H), 4.37-4.31 (m, 2H), 4.17-4.13 (m, 1H), 3.72 (br s,1H), 3.24 (brt, J=10.1 Hz, 1H), 2.28-2.00 (m, 3H), 1.44 (s, 10H).

Example 1:2-(4-chlorophenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide

((2-(trifluoromethoxy)ethoxy)methyl)benzene: To a mixture of AgOTf (50.7g, 197.1 mmol) in EtOAc (380 mL) under a nitrogen atmosphere were added1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (52.4 g, 147.8 mmol), KF (17.2 g, 295.7 mmol), and2-benzyloxyethanol (15.0 g, 98.6 mmol) in light resistant containerfollowed by the addition of 2-fluoropyridine (16.9 mL, 197.1 mmol) andtrimethyl(trifluoromethyl)silane (28.0 g, 197.1 mmol). The reactionmixture was stirred at 30° C. for 16 h. The reaction mixture wasfiltered through a pad of celite to give filtrate that was concentratedunder reduced pressure. The crude residue was purified by silica gelcolumn chromatography to give the desired product. ¹H-NMR (400 MHz,CDCl₃): δ 7.40-7.28 (m, 5H), 4.60 (s, 2H), 4.16-4.10 (m, 2H), 3.74-3.67(m, 2H).

2-(trifluoromethoxy)ethanol: To a suspension of palladium (500 mg, 10%purity on carbon) in EtOAc (10 mL) was added((2-(trifluoromethoxy)ethoxy)methyl)benzene (2.0 g, 9.08 mmol). Thereaction mixture was stirred at 35° C. for 24 h under H₂ (50 psi). Thereaction mixture was filtered through celite to give filtrate that wasconcentrated under reduced pressure. The crude residue was useddirectly. ¹H-NMR (400 MHz, CDCl₃): δ 4.00-3.96 (m, 2H), 3.76 (t, J=4.5Hz, 2H).

methyl(2S,5R)-5-(tert-butoxycarbonylamino)tetrahydropyran-2-carboxylate: To amixture of(2S,5R)-5-(tert-butoxycarbonylamino)tetrahydropyran-2-carboxylic acid(245 mg, 1.00 mmol) in DCM (4.0 mL) was added(trimethylsilyl)diazomethane (1.00 mL, 2.00 mmol, 2 M in hexanes)dropwise. The reaction mixture was stirred at 23° C. for 1 h and thenconcentrated under reduced pressure. The crude residue was useddirectly.

methyl (2R,5S)-5-aminotetrahydropyran-2-carboxylate: To a mixture ofmethyl (2R,5S)-5-(tert-butoxycarbonylamino)tetrahydropyran-2-carboxylate(1.05 g, 4.05 mmol) in DCM (13 mL) at 0° C. was added trifluoroaceticacid (3.1 mL, 40.5 mmol). The reaction mixture was stirred at 23° C. for4 h and then the volatiles were removed under reduced pressure. Theresidue was then diluted with DCM (30 mL) and poured onto sat. aq.NaHCO₃ (50 mL). The organics were separated and the aqueous wasextracted with using a 3:1 mixture of DCM:i-PrOH (3×30 mL). The combinedorganics were dried of anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The residue was used directly. LCMS: m/z=160.2 [M+H]⁺.

methyl(2S,5R)-5-[[2-(4-chlorophenoxy)acetyl]amino]tetrahydropyran-2-carboxylate:Prepared using General Procedure A employing methyl(2S,5R)-5-aminotetrahydropyran-2-carboxylate (644 mg, 4.05 mmol),2-(4-chlorophenoxy)acetic acid (906 mg, 4.85 mmol), Et₃N (2.82 mL, 20.2mmol), and T3P solution (7.23 mL, 12.1 mmol, 50% in EtOAc) in EtOAc(10.1 mL). The crude residue was purified by silica gel columnchromatography to give the desired product. LCMS: m/z=328.3 [M+H]⁺.

2-(4-chlorophenoxy)-N-((3R,6S)-6-(hydrazinecarbonyl)tetrahydropyran-3-yl)acetamide:Prepared using General Procedure B employing methyl(2S,5R)-5-[[2-(4-chlorophenoxy)acetyl]amino]tetrahydropyran-2-carboxylate(622 mg, 1.9 mmol) and hydrazine hydrate in EtOH (12.7 mL). The reactionmixture was concentrated under reduced pressure and the crude residuewas used directly. LCMS: m/z=328.3 [M+H]⁺.

2-(trifluoromethoxy)ethyl2-((2S,5R)-5-(2-(4-chlorophenoxy)acetamido)tetrahydro-2H-pyran-2-carbonyl)hydrazinecarboxylate:To a solution of 2-(trifluoromethoxy)ethanol (100 mg, 0.76 mmol) andtriphosgene (46 mg, 0.15 mmol) in THF (2.0 mL) at 0° C. was addedpyridine (91 mg, 1.15 mmol) dropwise. The reaction mixture was stirredat 20° C. for 1 h and then2-(4-chlorophenoxy)-N-((3R,6S)-6-(hydrazinecarbonyl)tetrahydro-2H-pyran-3-yl)acetamide(126 mg, 0.38 mmol) was added. The resultant mixture was stirred at 20°C. for a further 15 h. The reaction mixture quenched by the addition ofH2O (10 mL) and extracted with EtOAc (2×5 mL). The combined organicswere washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. The crude residue was purifiedemploying reverse-phase HPLC to give the desired product. LCMS:m/z=484.1 [M+H]⁺.

2-(4-chlorophenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide:To a solution of 2-(trifluoromethoxy)ethyl2-((2S,5R)-5-(2-(4-chlorophenoxy)acetamido)tetrahydro-2H-pyran-2-carbonyl)hydrazinecarboxylate(50 mg, 0.10 mmol) in MeCN (2.0 mL) was added p-TsCl (79 mg, 0.41 mmol)and Cs₂CO₃ (202 mg, 0.62 mmol). The reaction mixture was stirred at 15°C. for 16 h. The reaction mixture was poured onto ice-water (15 mL) andthe aqueous was extracted with EtOAc (3×5 mL). The organic layers werewashed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude residue was purifiedemploying reverse-phase HPLC to give the desired product. LCMS:m/z=466.1 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 7.33-7.28 (m, 2H),6.90-6.85 (m, 2H), 6.46 (br d, J=7.7 Hz, 1H), 4.75-4.69 (m, 2H),4.62-4.57 (m, 1H), 4.47 (s, 2H), 4.37-4.32 (m, 2H), 4.22-4.10 (m, 2H),3.41-3.34 (m, 1H), 2.31-2.21 (m, 1H), 2.16-2.06 (m, 2H), 1.72-1.62 (in,1H).

Examples 2-5

The following compounds were, or can be, made via similar procedures asthose described above.

LCMS Ex. Structure m/z ([M + H]⁺) 2

500.3 3

466.1 4

482.2 5

521.5

Example 6:N-[(3R,6S)-6-[5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl]tetrahydropyran-3-yl]-6-(trifluoromethyl)quinoxaline-2-carboxamide

N-[(3R,6S)-6-[5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl]tetrahydropyran-3-yl]-6-(trifluoromethyl)quinoxaline-2-carboxamidewas prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(50 mg, 0.122 mmol), 6-(trifluoromethyl)quinoxaline-2-carboxylic acid(35.4 mg, 0.146 mmol), NEt₃ (61.5 mg, 0.61 mmol) and T3P solution (77mg, 0.243 mmol, 0.145 mL, 50% in EtOAc) in EtOAc (0.82 mL) at 25° C. for16 h. The residue was purified by reverse-phase HPLC to give the desiredproduct. LC-MS: m/z=522.2. ¹H-NMR (400 MHz; CDCl₃): δ 8.54 (s, 1H), 8.31(d, J=8.8 Hz, 1H), 8.06 (dd, J=8.9, 2.0 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H),4.77-4.70 (m, 3H), 4.41-4.28 (m, 4H), 3.58 (dd, J=11.1, 8.8 Hz, 1H),2.46-2.40 (m, 1H), 2.30-2.17 (m, 2H), 1.93-1.84 (in, 1H).

Examples 7-20

The following compounds were, or can be, made via similar procedures asthose described above.

LCMS Ex. Structure m/z ([M + H]⁺) 7

506.1 8

9

10

11

12

13

14

15

16

17

18

19

20

Example 21:2-(4-chlorophenoxy)-N-((3R,6S)-6-(5-(3-(trifluoromethoxy)propyl)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide

4-(trifluoromethoxy)butanoic acid: To a flask in the dark were added KF(3.55 g, 60.0 mmol), SelectFluor (15.9 g, 45.0 mmol), AgOTf (11.6 g,45.0 mmol), and tert-butyl 4-hydroxybutanoate (2.4 g, 15.0 mmol). Themixture was then dissolved in EtOAc (73 mL) followed by the addition of2-fluoropyridine (3.87 mL, 45.0 mmol) andtrimethyl(trifluoromethyl)silane (6.65 mL, 45.0 mmol). The reactionmixture was stirred for 16 h at 23° C. and then filtered through a plugof celite and concentrated under reduced pressure. The residue wassuspended in 1:1 mixture of Et₂O and hexanes. The suspension wasfiltered through a pad of silica and was concentrated under reducedpressure. The residue was dissolved in DCM (10 mL) and TFA (10 mL) at23° C. and was stirred for 4 h. The mixture was then concentrated underreduced pressure and the residue was partitioned between Et₂O (25 mL)and water (25 mL). The layers were separated and the aqueous layer wasextracted with Et₂O (3×10 mL). The combined organic layers were driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressure.The crude residue was used directly.

2-(4-chlorophenoxy)-N-[(3S,6R)-6-[[4-(trifluoromethoxy)butanoylamino]carbamoyl]tetrahydropyran-3-yl]acetamide:2-(4-chlorophenoxy)-N-[(3S,6R)-6-(hydrazinecarbonyl)tetrahydropyran-3-yl]acetamide(400 mg, 1.22 mmol) was suspended in MeCN (12.2 mL) and4-(trifluoromethoxy)butanoic acid (315 mg, 1.83 mmol), NEt₃ (0.85 mL,6.1 mmol), and T3P solution (1.09 mL, 3.66 mmol, 50% in EtOAc) wereadded. The resulting reaction mixture was stirred at 23° C. for 12 h.The reaction mixture was quenched by the addition of sat. aq. NaHCO₃ (5mL) and DCM (10 mL). The layers were separated and the aqueous layer wasextracted with 3:1 DCM:i-PrOH (3×10 mL). The combined organic layerswere dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude residue was used directly.

2-(4-chlorophenoxy)-N-((3R,6S)-6-(5-(3-(trifluoromethoxy)propyl)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide:2-(4-chlorophenoxy)-N-[(3R,6S)-6-[[4-(trifluoromethoxy)butanoylamino]carbamoyl]tetrahydropyran-3-yl]acetamide(588 mg, 1.22 mmol) was suspended in MeCN (5.5 mL) and p-TsCl (558 mg,2.93 mmol) and Cs₂CO₃ (1.60 g, 4.88 mmol) were added. The reactionmixture was stirred overnight at 80° C. The reaction mixture was dilutedwith brine (10 mL) and EtOAc (10 mL). The layers were separated and theaqueous layer was extracted with EtOAc (3×10 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude reaction mixture was purified employingsilica gel column chromatography and then further purified byreverse-phase preparative HPLC to provide the desired product. LCMS: mz=464.4 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 7.33-7.29 (m, 2H), 6.91-6.87(m, 2H), 6.47 (d, J=8.0 Hz, 1H), 4.72 (dd, J=9.1, 3.8 Hz, 1H), 4.48-4.47(m, 2H), 4.22-4.11 (m, 4H), 3.42-3.37 (m, 1H), 3.03 (t, J=7.4 Hz, 2H),2.31-2.09 (m, 5H), 1.74-1.66 (m, 1H).

Example 22:N-[(3S,6R)-6-[5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl]tetrahydropyran-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide

N-[(3S,6R)-6-[[4-(trifluoromethoxy)butanoylamino]carbamoyl]tetrahydropyran-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide:N-[(3S,6R)-6-(hydrazinecarbonyl)tetrahydropyran-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide(150 mg, 0.42 mmol) was suspended in MeCN (4.5 mL) and4-(trifluoromethoxy)butanoic acid (107 mg, 0.62 mmol) and NEt₃ (0.29 mL,2.1 mmol) and T3P solution (0.37 mL, 1.25 mmol, 50% in EtOAc) wereadded. The resulting reaction mixture was stirred at 23° C. for 12 h.The reaction mixture was quenched by the addition of sat. aq. NaHCO₃ (5mL) and DCM (10 mL). The layers were separated and the aqueous layer wasextracted with 3:1 DCM:i-PrOH (3×10 mL). The combined organic layerswere dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude residue was purified by silica gelchromatography.

N-[(3S,6R)-6-[5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl]tetrahydropyran-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide:N-[(3S,6R)-6-[[4-(trifluoromethoxy)butanoylamino]carbamoyl]tetrahydropyran-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide(180 mg, 0.35 mmol) was suspended in MeCN (1.7 mL) and p-TsCl (160 mg,0.84 mmol) and Cs₂CO₃ (458 mg, 1.4 mmol) were added. The reactionmixture was stirred at 80° C. for 16 h. The reaction mixture was dilutedwith brine (10 mL) and EtOAc (10 mL). The layers were separated and theaqueous layer was extracted with EtOAc (3×10 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude reaction mixture was purified employingreverse-phase preparative HPLC to provide the desired product. LCMS: mz=498.4 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 7.63-7.61 (m, 2H), 7.03 (dd,J=9.0, 0.6 Hz, 2H), 6.49 (d, J=7.8 Hz, 1H), 4.72 (dd, J=9.1, 3.8 Hz,1H), 4.56 (s, 2H), 4.24-4.15 (m, 2H), 4.12 (t, J=6.0 Hz, 2H), 3.44-3.38(m, 1H), 3.03 (dd, J=8.2, 6.6 Hz, 2H), 2.32-2.10 (m, 5H), 1.76-1.66 (m,1H).

Example 23:6-chloro-7-fluoro-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)quinoline-2-carboxamide

Prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(50 mg, 0.168 mmol), 6-chloro-7-fluoroquinoline-2-carboxylic acid (45.54mg, 0.201 mmol), NEt₃ (68.09 mg, 0.672 mmol) and T3P solution (321.14mg, 0.504 mmol, 0.300 mL, 50% in EtOAc) in EtOAc (2 mL) at 25° C. for 16h. The residue was purified by prep-HPLC with the following conditions:column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 45%-75%, 8 min to give the desiredproduct. LC-MS: m/z=505.1, 507.1 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ8.33-8.24 (m, 2H), 8.10 (br d, J=7.6 Hz, 1H), 7.98 (d, J=7.7 Hz, 1H),7.87 (d, J=9.7 Hz, 1H), 4.76-4.71 (m, 2H), 4.68 (dd, J=3.7, 9.1 Hz, 1H),4.39-4.34 (m, 2H), 4.34-4.26 (m, 2H), 3.57-3.50 (m, 1H), 2.40 (br d,J=12.1 Hz, 1H), 2.29-2.13 (m, 2H), 1.91-1.78 (m, 1H).

Example 24:N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)-6-(trifluoromethyl)quinazoline-2-carboxamide

Prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(59 mg, 0.20 mmol), 6-(trifluoromethyl)quinazoline-2-carboxylic acid (48mg, 0.20 mmol), DIEA (103 mg, 0.79 mmol) and T3P solution (253 mg, 0.40mmol, 0.24 mL, 50% in EtOAc) in EtOAc (5 mL) for 5 h at 20° C. Theresidue was purified by silica gel column chromatography (PE:EtOAc=1:0to 0:1) to give the desired product. LC-MS: m/z=522.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): δ 9.64 (s, 1H), 8.43-8.36 (m, 2H), 8.27-8.16 (m, 2H),4.78-4.61 (m, 3H), 4.44-4.27 (m, 4H), 3.54 (dd, J=8.9, 11.1 Hz, 1H),2.47-2.36 (m, 1H), 2.28-2.11 (m, 2H), 1.93-1.78 (m, 1H).

Example 25:2-(4-bromophenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide

(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine:To tert-butyl((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(50 mg, 0.13 mmol) in DCM (2 mL) was added TFA (440 mg, 3.86 mmol, 0.29mL) at 25° C., and the mixture was stirred for 2 h. The reaction mixturewas diluted with sat. NaHCO₃ (10 mL), and was extracted with DCM (2×10mL). The combined organic layers were washed with brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give the title compound.

2-(4-bromophenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide:Prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(30 mg, 0.10 mmol), 2-(4-bromophenoxy)acetic acid (28 mg, 0.12 mmol),NEt₃ (41 mg, 0.40 mmol) and T3P solution (193 mg, 0.30 mmol, 0.18 mL,50% in EtOAc) in EtOAc (2 mL) at 25° C. for 16 h. The residue waspurified by prep-HPLC with the following conditions: column: WatersXbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 40%-70%, 10 min to give the title compound. LCMS:m/z=510.1, 512.1 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 7.44 (d, J=8.8 Hz,2H), 6.83 (d, J=8.9 Hz, 2H), 6.45 (br d, J=7.9 Hz, 1H), 4.75-4.69 (m,2H), 4.60 (t, J=6.3 Hz, 1H), 4.47 (s, 2H), 4.38-4.31 (m, 2H), 4.14 (brd, J=8.2 Hz, 2H), 3.37 (brt, J=10.9 Hz, 1H), 2.26 (br d, J=12.1 Hz, 1H),2.17-2.09 (m, 2H), 1.66 (br s, 1H).

Example 26:2-(3-fluoro-4-(trifluoromethyl)phenoxy)-N-((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide

tert-butyl((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a solution of 2-(2,2,2-trifluoroethoxy)ethanol (40 mg, 0.28 mmol) inTHF (2.0 mL) was added NaH (13.3 mg, 0.33 mmol, 60% in mineral oil) at0° C., and the mixture was stirred at 0° C. for 30 min. tert-ButylN-[(3R,6S)-6-(5-methylsulfonyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-3-yl]carbamate(96.43 mg, 0.28 mmol) was added at 0° C., and the mixture was stirred at18° C. for 2 h. The mixture was poured into sat. NH₄Cl solution (10 mL).The aqueous phase was extracted with EtOAc (3×8 mL). The combinedorganic phases were washed with brine (5 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, PE:EtOAc=1:3) to give the titlecompound. ¹H-NMR (400 MHz, CDCl₃): δ 4.69-4.61 (m, 2H), 4.55-4.42 (m,2H), 4.17-4.11 (m, 1H), 4.04-3.99 (m, 2H), 3.92 (q, J=8.6 Hz, 2H), 3.73(br s, 1H), 3.25 (brt, J=10.1 Hz, 1H), 2.29-2.16 (m, 1H), 2.15-1.98 (m,2H), 1.57-1.42 (m, 10H).

(3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine:To a solution of tert-butyl((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(54 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.4 mL) and stirred at20° C. for 1 h. The mixture was concentrated under reduced pressure togive the desired product.

2-(3-fluoro-4-(trifluoromethyl)phenoxy)-N-((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide:Prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(40 mg, 0.13 mmol), 2-[3-fluoro-4-(trifluoromethyl)phenoxy]acetic acid(31 mg, 0.13 mmol), DIEA (67 mg, 0.51 mmol) and T3P (164 mg, 0.26 mmol,50% in EtOAc) in EtOAc (2 mL) for 16 h at 20° C. The mixture waspurified by p-HPLC with the following conditions: column: Waters XbridgeBEH C18 100*25 mm*5 m; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:30%-60%, 10 min to give the title compound. LCMS: m/z=532.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ 7.59 (t, J=8.3 Hz, 1H), 6.80 (br d, J=9.9 Hz,2H), 6.40 (br d, J=7.7 Hz, 1H), 4.69-4.64 (m, 2H), 4.61 (t, J=6.2 Hz,1H), 4.53 (s, 2H), 4.23-4.11 (m, 2H), 4.05-4.00 (m, 2H), 3.93 (q, J=8.6Hz, 2H), 3.43-3.35 (m, 1H), 2.33-2.22 (m, 1H), 2.18-2.07 (m, 2H),1.71-1.62 (m, 1H).

Example 27:2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3R,6S)-6-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]tetrahydropyran-3-yl]acetamide

Prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(200 mg, 0.650 mmol), 2-[3-fluoro-4-(trifluoromethyl)phenoxy]acetic acid(186 mg, 0.781 mmol), NEt₃ (329 mg, 3.25 mmol) and T3P solution (414 mg,1.30 mmol, 0.300 mL, 50% in EtOAc) in EtOAc (3.5 mL) at 25° C. for 16 h.The residue was purified by column chromatography (0→100% EtOAc/hexanes)and then recrystallized from diethyl ether to give the desired product.LC-MS: m/z=518.71. ¹H-NMR (400 MHz; CDCl₃): δ 7.60 (t, J=8.3 Hz, 1H),6.82 (s, 1H), 6.80 (s, 1H), 6.42 (d, J=7.7 Hz, 1H), 4.75-4.72 (m, 2H),4.64-4.61 (m, 1H), 4.54 (s, 2H), 4.37-4.35 (m, 2H), 4.22-4.14 (m, 2H),3.43-3.38 (m, 1H), 2.32-2.25 (m, 1H), 2.14 (dt, J=9.7, 5.1 Hz, 2H),1.74-1.63 (m, 1H).

Example 28:N-((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)-2-(4-(trifluoromethyl)phenoxy)acetamide

2-(2,2,2-trifluoroethoxy)ethyl2-((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carbonyl)hydrazinecarboxylate:To a solution of 2-(2,2,2-trifluoroethoxy)ethanol (300 mg, 2.08 mmol) inTHF (5 mL) was added bis(trichloromethyl) carbonate (216 mg, 0.73 mmol),followed by dropwise pyridine (988 mg, 12.49 mmol, 1.01 mL) at 0° C.under N₂. The mixture was stirred at 20° C. for 2 h. The mixture wasadded tert-butylN-[(3R,6S)-6-(hydrazinecarbonyl)tetrahydropyran-3-yl]carbamate (378 mg,1.46 mmol) at 20° C. and stirred for 14 h. The mixture was poured intoice-water (45 mL), extracted with EtOAc (3×15 mL). The combined organiclayers were washed with brine (15 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford the desiredproduct. LCMS: m/z=374.1 [M+H]¹. ¹H NMR (400 MHL-z, DMSO-d₆): δ 9.57 (brs, 1H), 9.10 (br s, 1H), 6.82 (br d, J=7.8 Hz, 1H), 4.17-4.05 (m, 4H),3.92-3.68 (m, 4H), 3.42-3.34 (m, 1H), 3.07-2.94 (m, 1H), 1.89 (br d,J=7.9 Hz, 2H), 1.54-1.41 (m, 2H), 1.38 (s, 9H).

tert-butyl((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a solution of 2-(2,2,2-trifluoroethoxy)ethyl2-((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carbonyl)hydrazinecarboxylate(600 mg, 1.40 mmol) in MeCN (10 mL) was added Cs₂CO₃ (1.82 g, 5.59 mmol)and p-TsCl (533 mg, 2.79 mmol) at 20° C. under N₂. The mixture wasstirred for 16 h. The mixture was poured onto water (30 mL), and wasextracted with EtOAc (3×15 mL). The combined organic layers were washedwith brine (15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=1:0 to 0:1) to give the desiredproduct. LCMS: m/z=412.2 [M+H]¹. ¹H NMR (400 MHL-z, CDCl₃): δ 4.69-4.61(m, 2H), 4.56-4.48 (m, 1H), 4.45 (br s, 1H), 4.19-4.13 (m, 1H),4.06-3.98 (m, 2H), 3.97-3.87 (m, 2H), 3.81-3.62 (m, 1H), 3.25 (br t,J=10.3 Hz, 1H), 2.28-2.18 (m, 1H), 2.16-2.07 (m, 1H), 1.46 (s, 11H).

(3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine:To a solution of tert-butyl((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(110 mg, 0.27 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 20° C., andthe mixture was stirred for 1 h. The mixture was concentrated underreduced pressure, the residue was poured into water, adjusted to pH=8 byaddition of NH₃.H₂O, and was extracted with DCM:i-PrOH (3×5 mL,v:v=3:1). The combined organic layers were washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give the desired product.

N-((3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)-2-(4-(trifluoromethyl)phenoxy)acetamide:Prepared employing General Procedure A employing(3R,6S)-6-(5-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine(83 mg, 0.27 mmol), 2-[4-(trifluoromethyl)phenoxy]acetic acid (59 mg,0.27 mmol), DIEA (207 mg, 1.60 mmol, 0.28 mL) and T3P (509 mg, 0.80mmol, 0.48 mL, 5000 in EtOAc) in EtOAc (3 mL) at 20° C. for 5 h. Themixture was purified by p-TLC (PE:EtOAc=0:1) to give the title compound.LCMS: m/z=514.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO): δ 7.61 (d, J=8.7 Hz,2H), 7.02 (d, J=8.7 Hz, 2H), 6.48 (br d, J=7.7 Hz, 1H), 4.68-4.62 (m,2H), 4.62-4.56 (m, 1H), 4.54 (s, 2H), 4.23-4.10 (m, 2H), 4.06-3.98 (m,2H), 3.92 (q, J=8.6 Hz, 2H), 3.43-3.32 (m, 1H), 2.30-2.20 (m, 1H),2.16-2.04 (m, 2H), 1.70-1.61 (m, 1H).

Examples 29-31

The following compounds were, or can be, made via similar procedures asthose described above.

LCMS Ex. Structure m/z ([M + H]⁺) 29

539.0 30

540.1 31

540.1

Example 32:N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)-6-(trifluoromethyl)quinoxaline-2-carboxamide(32)

tert-butyl((3R,6S)-6-(5-mercapto-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a mixture of tert-butyl((3R,6S)-6-(hydrazinecarbonyl)tetrahydro-2H-pyran-3-yl)carbamate (7.6 g,29.3 mmol) in MeOH (60 mL) was added KOH (4.11 g, 73.3 mmol) at 25° C.under N₂. The mixture was stirred at 25° C. for 0.5 h, CS₂ (8.93 g, 117mmol, 7.08 mL) was added, and the mixture was stirred at 80° C. for 15.5h. The reaction mixture was concentrated under reduced pressure to givea residue. The residue was added H₂O (250 mL) at 25° C. and thenadjusted to pH=3 with HCl (3 M). The mixture was filtered and thefiltered cake was concentrated under reduced pressure to give the titlecompound.

tert-butyl((3R,6S)-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a solution of tert-butyl((3R,6S)-6-(5-mercapto-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(5.0 g, 15.8 mmol) in DMF (40 mL) was added K₂CO₃ (4.35 g, 31.5 mmol) at0° C. under N₂. Mel (4.47 g, 31.5 mmol) was added drop-wise at 0° C.,and the mixture was stirred at 25° C. for 15 h. The mixture was pouredinto water (150 mL), and the aqueous phase was extracted with EtOAc(3×30 mL). The combined organic phases were washed with brine (10 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=50:1 to 1:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃): δ 4.71 (dd, J=2.4, 10.7 Hz, 1H), 4.40 (br s, 1H), 4.19 (ddd,J=2.0, 4.4, 11.0 Hz, 1H), 3.70 (br d, J=5.6 Hz, 1H), 3.30-3.18 (m, 1H),2.77 (s, 3H), 2.33 (br dd, J=2.8, 13.6 Hz, 1H), 2.25-2.16 (m, 1H),1.89-1.75 (m, 1H), 1.45 (m, 10H).

tert-butyl((3R,6S)-6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a solution of tert-butyl((3R,6S)-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(1.6 g, 4.83 mmol) in DCM (30 mL) was added m-CPBA (5.21 g, 24.1 mmol,80% purity) at 0° C. The mixture was stirred at 25° C. for 15 h. Themixture was poured into sat. Na₂S2O₃ (30 mL) and then adjusted to pH=7-8with sat.NaHCO₃. The aqueous phase was extracted with DCM (3×15 mL). Thecombined organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=20:1to 1:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃): δ 4.81 (dd,J=2.8, 11.2 Hz, 1H), 4.36 (br s, 1H), 4.31-4.22 (m, 1H), 3.76 (br d,J=13.2 Hz, 1H), 3.46 (s, 3H), 3.27 (t, J=10.8 Hz, 1H), 2.50-2.42 (m,1H), 2.30-2.20 (m, 1H), 1.88-1.74 (m, 1H), 1.57-1.52 (m, 1H), 1.46 (s,9H).

tert-butyl((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate:To a solution of 2-(trifluoromethoxy)ethanol (180 mg, 1.38 mmol) in THF(5 mL) was added NaH (66 mg, 1.66 mmol, 60% in mineral oil) at 0° C.,and the mixture was stirred at 0° C. for 30 min. Then tert-butyl((3R,6S)-6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(502 mg, 1.38 mmol) was added at 0° C., and the mixture was stirred at25° C. for 1 h. The mixture was poured into sat. NH₄Cl (15 mL), theaqueous phase was extracted with EtOAc (3×8 mL). The combined organicphases were washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 4.77-4.71 (m, 2H), 4.60 (dd, J=2.8,10.8 Hz, 1H), 4.42-4.31 (m, 3H), 4.21-4.14 (m, 1H), 3.72 (br s, 1H),3.21 (t, J=10.8 Hz, 1H), 2.30 (br dd, J=2.8, 13.6 Hz, 1H), 2.25-2.16 (m,1H), 1.89-1.76 (m, 1H), 1.55-1.43 (m, 10H).

(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-amine:To a solution of tert-butyl((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(100 mg, 0.24 mmol) in DCM (5.0 mL) was added TFA (1.0 mL), and themixture was stirred at 25° C. for 1 h. The mixture was adjusted topH=7-8 with sat. NaHCO₃. The aqueous phase was extracted with DCM/i-PrOH(3×5 mL, v:v=3:1). The combined organic phases were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound.

N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)-6-(trifluoromethyl)quinoxaline-2-carboxamide:To a solution of(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-amine(60 mg, 0.19 mmol) and 6-(trifluoromethyl)quinoxaline-2-carboxylic acid(46 mg, 0.19 mmol) in EtOAc (5 mL) was added T3P solution (0.38 mmol,0.23 mL, 50% in EtOAc) and DIEA (99 mg, 0.76 mmol), and the mixture wasstirred at 25° C. for 2 h. The mixture was poured into water (15 mL).The aqueous phase was extracted with EtOAc (3×5 mL). The combinedorganic phase was washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (neutral) under the following conditions: column:Welch Xtimate C18 150*25 mm*5 m; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 45%-70%, 10 min to give the title compound. LC-MS:m/z: 538.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.78 (s, 1H), 8.53 (s,1H), 8.28 (d, J=8.8 Hz, 1H), 8.05 (dd, J=1.6, 8.8 Hz, 1H), 7.82 (br d,J=7.6 Hz, 1H), 4.81-4.70 (m, 3H), 4.44-4.27 (m, 4H), 3.58-3.45 (m, 1H),2.49-2.30 (m, 2H), 2.05-1.93 (m, 1H), 1.92-1.80 (m, 1H).

Example 33:2-(3-fluoro-4-(trifluoromethyl)phenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide(33)

2-(3-fluoro-4-(trifluoromethyl)phenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide:To a solution of(3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-amine(75 mg, 0.24 mmol) in EtOAc (3.0 mL) was added2-[3-fluoro-4-(trifluoromethyl)phenoxy]acetic acid (57 mg, 0.24 mmol),DIEA (124 mg, 0.96 mmol, 0.17 mL) and T3P solution (305 mg, 0.48 mmol,0.28 mL, 50% in EtOAc) at 0° C. under N₂. The mixture was stirred at 25°C. for 2 h. The mixture was poured into NaHCO₃ (30 mL), extracted withEtOAc (3×10 mL). The combined organic layers were washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by p-HPLC (neutral) under thefollowing conditions: column: Welch Xtimate C18 150×25 mm×5 m; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 45%-70%, 10 min to give2-(3-fluoro-4-(trifluoromethyl)phenoxy)-N-((3R,6S)-6-(5-(2-(trifluoromethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-3-yl)acetamide.LCMS: m/z=534.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.58 (t, J=8.3 Hz,1H), 6.79 (d, J=9.9 Hz, 2H), 6.30 (br d, J=7.9 Hz, 1H), 4.78-4.72 (m,2H), 4.67 (dd, J=2.8, 10.4 Hz, 1H), 4.53 (s, 2H), 4.38-4.32 (m, 2H),4.24-4.11 (m, 2H), 3.39-3.29 (m, 1H), 2.37-2.29 (m, 1H), 2.28-2.19 (m,1H), 1.97-1.84 (m, 1H), 1.72-1.62 (m, 1H).

Biological Example 1 Biochemical Assay of the Compounds

Cellular stress leads to activation of the integrated stress responsepathway through one of four eukaryotic initiation factor 2a kinases andhalts global translation, while allowing for the translation of selecttranscripts like ATF4 (activating transcription factor 4) that areimportant for the response to cellular stress. During normal conditions,small open reading frames (ORFs) in the 5′ UTR of ATF4 occupy theribosome and prevent translation of the coding sequence of ATF4. Duringstress conditions however, the ribosome scans past these upstream ORFsand preferentially begins translation at the coding sequence of ATF4. Inthis way, the translation, and thus protein level of ATF4 is a readoutof ISR pathway activation. Thus, a fusion of the uORFs and the beginningof the coding sequence of ATF to a common cellular reporter likenano-luciferase allows for a sensitive and high-throughput readout ofISR pathway activity.

Compounds as provided herein were tested in the following assay. TheATF4 Nano Luciferase reporter was constructed by fusing the human fulllength 5′ untranslated region (5′-UTR) and a small portion of the codingsequence of the ATF4 gene upstream of the Nano Luciferase (NLuc) codingsequence lacking it's start codon. Specifically, nucleotides +1 through+364 (relative to the transcriptional start site) of ATF4 transcriptvariant 2 (NCBI NM_182810.2) flanked 5′ by EcoRI and 3′ by BamHIrestriction enzyme sites were synthesized and cloned into theEcoRI/BamHI cloning sites of pLVX-EF1a-IRES-Puro lentivirus vector(Clontech). Lentiviral particles were produced with Lenti-X single shots(VSV-G, Clontech) according to the manufacturer's instructions and usedto transduce a human H4 neuroglioma cell line (ATCC HTB-148). H4 cellswere selected with 1.25 μg/mL Puromycin, and clonal cell lines generatedby limiting dilution. This cell line was utilized to generate anintegrated stress response (ISR) assay to evaluate the activity of ISRpathway inhibitors via luminescence readout. The H4 ATF4-NLuc (clone 17)cell line was plated at a density of 15,000 or 2.50 cells in 96-well or384-well respectively in DMEM+10% fetal bovine serum. 24-hours latertest compounds diluted in dimethyl sulfoxide (DMSO) were added for 30minutes at 37° C., followed by ISR pathway activation with 50 μm sodiumarsenite aqueous solution for 6 additional hours. Nano Glo luciferasereagent (N1150, Promega) was added according to manufacturerinstructions and the luminescence signal (corresponding to the level ofATF4 translation and thus ISR pathway activation) was read with astandard plate reader with luminescence detection capabilities.

In the table below, activity of the tested compounds is provided.

TABLE 3 Ex. Activity (nM) 1 1.2 2 5.0 3 11.4 4 53.2 5 13.6 6 11 7 3.8 217.9 22 14.9 23 1 24 27 25 2 26 7.9 27 1.2 28 15.5 29 1.4 30 2.8 31 7.232 173 33 5.9

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising,” “including,” “containing,” etc. shall be read expansivelyand without limitation.

Additionally, the terms and expressions employed herein have been usedas terms of description and not of limitation, and there is no intentionin the use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

1. A compound of Formula I:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:ring A is C₃₋₁₀ cycloalkyl or heterocyclyl, provided ring A is not abicyclo[1.1.1]pentane or bicyclo[2.1.1]hexane; wherein each isoptionally substituted with one to six R¹⁴; ring B is a 5- or 6-memberedheteroaryl or phenyl; wherein each is optionally substituted with one tothree R¹³; Q¹ and Q² are each independently O, S or NR¹⁵; L is a C₁₋₆alkylene linker, optionally substituted with one to three substituentsindependently selected from halo, cyano, nitro, —OR⁶, —SR⁶, —SF₅,—NR⁶R⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R⁶, —C(O)OR⁶,—OC(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶,—S(O)₁₋₂NR⁶, —NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, and—NR⁶C(O)OR⁷; z is 0 or 1; X¹ is O, NR⁹ or a bond; R¹ is hydrogen, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, or heterocyclyl,each of which, other than hydrogen, is optionally substituted with oneto three R¹¹; R² is C₁₋₆ haloalkyl; R³ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, orheteroaryl, each of which, other than hydrogen, is optionallysubstituted with one to five R¹¹; R⁴ and R⁵ are independently hydrogen,C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or C₂₋₁₂ alkynyl, each of which, other thanhydrogen, is independently optionally substituted with one to five R¹¹;or R³ and R⁴, together with the atoms to which they are attached, jointo form a C₃₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one to five R¹¹; or R⁴ and R⁵, together with the atomsto which they are attached, join to form a C₃₋₁₀ cycloalkyl orheterocyclyl, each of which is optionally substituted with one to fiveR¹¹; each of R⁶, R⁷, and R⁸ is independently hydrogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl,heteroaryl, —C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰R²¹, —S(O)₁₋₂R²⁰ or—S(O)₁₋₂NR²⁰, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R⁶, R⁷, and R⁸ is independentlyoptionally substituted with one to five R¹²; or two of R⁶, R⁷, and R⁸are taken together with the atoms to which they are attached to formheterocyclyl independently optionally substituted by one to three halo,oxo, or C₁₋₁₂ alkyl independently optionally substituted by one to threeoxo, halo, hydroxyl, or amino; R⁹ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, or heterocyclyl, each ofwhich, other than hydrogen, is optionally substituted with one to threeR¹¹; each R¹¹ is independently halo, cyano, nitro, oxo, —OR⁶, —SR⁶,—SF₅, —NR⁶R⁷, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R⁶, —C(O)OR⁶,—OC(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶,—S(O)₁₋₂NR⁶, —NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, or—NR⁶C(O)OR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl of R¹¹ is independently optionallysubstituted with one to five R¹²; each R¹² is independently halo, cyano,nitro, oxo, —OR³⁰, —SR³⁰, —SF₅, —NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl,—C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰, —OC(O)R³⁰, —C(O)NR³⁰R³¹, —OC(O)NR³⁰R³¹,—NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰, —S(O)₁₋₂NR³⁰, —NR³⁰S(O)₁₋₂R³¹,—NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or —NR³⁰C(═O)OR³¹, wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylof R¹² is independently optionally substituted with one to three halo orC₁₋₁₂ alkyl independently optionally substituted by one to three oxo,halo, hydroxyl, or amino; each R¹³ is independently halo, cyano, nitro,oxo, —OR³⁰, —SR³⁰, —SF₅, —NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R³⁰,—C(O)OR³⁰, —OC(O)OR³⁰, —OC(O)R³⁰, —C(O)NR³⁰R³¹, —OC(O)NR³⁰R³¹,—NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰, —S(O)₁₋₂NR³⁰, —NR³⁰S(O)₁₋₂R³¹,—NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or —NR³⁰C(═O)OR³¹, wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylof R¹³ is independently optionally substituted with one to three halo orC₁₋₁₂ alkyl independently optionally substituted by one to three oxo,halo, hydroxyl, or amino; each R¹⁴ is independently halo, cyano, —NR⁶R⁷,C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ haloalkyl, or two R¹⁴ together with theatoms to which they are attached form a ring or a C═O; each R¹⁵ isindependently hydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; each R²⁰ and R²¹is independently hydrogen or C₁₋₁₂ alkyl independently optionallysubstituted with one to three oxo, halo, hydroxyl, or amino; or R²⁰ andR²¹ are taken together with the atoms to which they are attached to formheterocyclyl independently optionally substituted by one to three haloor C₁₋₁₂ alkyl independently optionally substituted by one to three oxo,halo, hydroxyl, or amino; and each R³⁰ and R³¹ is independently hydrogenor C₁₋₁₂ alkyl independently optionally substituted with one to threeoxo, halo, hydroxyl, or amino; or R³⁰ and R³¹ are taken together withthe atoms to which they are attached to form heterocyclyl independentlyoptionally substituted by one to three halo or C₁₋₁₂ alkyl independentlyoptionally substituted by one to three oxo, halo, hydroxyl, or amino. 2.The compound of claim 1, or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof, wherein ring A is monocyclic cycloalkyl, fused bicycliccycloalkyl, or spiro bicyclic cycloalkyl, wherein each is optionallysubstituted with one to six R¹⁴.
 3. The compound of claim 1, or apharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ringA is heterocyclyl, wherein each is optionally substituted with one tosix R¹⁴.
 4. The compound of claim 1, or a pharmaceutically acceptablesalt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein ring A is selected from

wherein each is independently optionally substituted with one to fourhalo.
 5. The compound of claim 1, or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof, wherein ring B is a five membered C₂₋₄ heteroaryl ringoptionally substituted with one to three R¹³.
 6. (canceled)
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, wherein ring B is

optionally independently substituted with one to three R¹³.
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, wherein ring B is a phenyl ring optionally independentlysubstituted with one to three R¹³.
 9. A compound of Formula II:

or a pharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: pis 0, 1, 2, 3, 4, 5 or 6; ring B is

wherein each is optionally substituted with one to three R¹³; Q¹ and Q²are each independently O, S or NR⁵; L is a C₁₋₆ alkylene linker,optionally substituted with one to three substituents independentlyselected from halo, cyano, nitro, —OR⁶, —SR⁶, —SF₅, —NR⁶R⁷, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R⁶, —C(O)OR⁶, —OC(O)OR⁶, —OC(O)R⁶,—C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶,—NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸, —NR⁶C(O)R⁷, and —NR⁶C(O)OR⁷; z is 0 or1; X¹ is O, NR⁹ or a bond; R¹ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, or heterocyclyl, each of which, otherthan hydrogen, is optionally substituted with one to three R¹¹; R² isC₁₋₆ haloalkyl; R³ is hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich, other than hydrogen, is optionally substituted with one to fiveR¹¹; R⁴ and R⁵ are independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl orC₂₋₁₂ alkynyl, each of which, other than hydrogen, is independentlyoptionally substituted with one to five R¹¹; or R³ and R⁴, together withthe atoms to which they are attached, join to form a C₃₋₁₀ cycloalkyl orheterocyclyl, each of which is optionally substituted with one to fiveR¹¹; or R⁴ and R⁵, together with the atoms to which they are attached,join to form a C₃₋₁₀ cycloalkyl or heterocyclyl, each of which isoptionally substituted with one to five R¹¹; each of R⁶, R⁷, and R⁸ isindependently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R²⁰, —C(O)OR²⁰,—C(O)NR²⁰R²¹, —S(O)₁₋₂R²⁰ or —S(O)₁₋₂NR²⁰, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R⁶, R⁷, andR⁸ is independently optionally substituted with one to five R¹²; or twoof R⁶, R⁷, and R⁸ are taken together with the atoms to which they areattached to form heterocyclyl independently optionally substituted byone to three halo, oxo, or C₁₋₁₂ alkyl independently optionallysubstituted by one to three oxo, halo, hydroxyl, or amino; R⁹ ishydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,or heterocyclyl, each of which, other than hydrogen, is optionallysubstituted with one to three R¹¹; each R¹¹ is independently halo,cyano, nitro, oxo, —OR⁶, —SR⁶, —SF₅, —NR⁶R⁷, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl,—C(O)R⁶, —C(O)OR⁶, —OC(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁷, —OC(O)NR⁶R⁷,—NR⁶C(O)NR⁷R⁸, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶, —NR⁶S(O)₁₋₂R⁷, —NR⁶S(O)₁₋₂NR⁷R⁸,—NR⁶C(O)R⁷, or —NR⁶C(O)OR⁷, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl of R¹¹ is independentlyoptionally substituted with one to five R¹²; each R¹² is independentlyhalo, cyano, nitro, oxo, —OR³⁰, —SR³⁰, —SF₅, —NR³⁰R³¹, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl,heteroaryl, —C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰, —OC(O)R³⁰, —C(O)NR³⁰R³¹,—OC(O)NR³⁰R³¹, —NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰, —S(O)₁₋₂NR³⁰,—NR³⁰S(O)₁₋₂R³¹, —NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or —NR³⁰C(═O)OR³¹,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl of R¹² is independently optionally substituted with oneto three halo or C₁₋₁₂ alkyl independently optionally substituted by oneto three oxo, halo, hydroxyl, or amino; each R¹³ is independently halo,cyano, nitro, oxo, —OR³⁰, —SR³⁰, —SF₅, —NR³⁰R³¹, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl,heteroaryl, —C(O)R³⁰, —C(O)OR³⁰, —OC(O)OR³⁰, —OC(O)R³⁰, —C(O)NR³⁰R³¹,—OC(O)NR³⁰R³¹, —NR³⁰C(O)NR³⁰R³¹, —S(O)₁₋₂R³⁰, —S(O)₁₋₂NR³⁰,—NR³⁰S(O)₁₋₂R³¹, —NR³⁰S(O)₁₋₂NR³⁰R³¹, —NR³⁰C(O)R³¹, or —NR³⁰C(═O)OR³¹,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl of R¹³ is independently optionally substituted with oneto three halo or C₁₋₁₂ alkyl independently optionally substituted by oneto three oxo, halo, hydroxyl, or amino; each R¹⁴ is independently halo,cyano, —NR⁶R⁷, C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ haloalkyl, or two R¹⁴together with the atoms to which they are attached form a ring or a C═O;each R¹⁵ is independently hydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; eachR²⁰ and R²¹ is independently hydrogen or C₁₋₁₂ alkyl independentlyoptionally substituted with one to three oxo, halo, hydroxyl, or amino;or R²⁰ and R²¹ are taken together with the atoms to which they areattached to form heterocyclyl independently optionally substituted byone to three halo or C₁₋₁₂ alkyl independently optionally substituted byone to three oxo, halo, hydroxyl, or amino; and each R³⁰ and R³¹ isindependently hydrogen or C₁₋₁₂ alkyl independently optionallysubstituted with one to three oxo, halo, hydroxyl, or amino; or R³⁰ andR³¹ are taken together with the atoms to which they are attached to formheterocyclyl independently optionally substituted by one to three haloor C₁₋₁₂ alkyl independently optionally substituted by one to three oxo,halo, hydroxyl, or amino.
 10. The compound of claim 1, or apharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ringB is optionally substituted with one to three R¹³, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, where each R¹³ is independently halo,cyano, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, or C₁₋₆ haloalkoxy.11. The compound of claim 1, or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof, wherein R² is —CHF₂, —CF₃ or —CH₂CF₃.
 12. The compoundof claim 1, or a pharmaceutically acceptable salt, isotopically enrichedanalog, stereoisomer, mixture of stereoisomers, or prodrug thereof,wherein Q¹ is O.
 13. (canceled)
 14. The compound of claim 1, or apharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Q¹is NR¹¹ and Q² is O.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein Q¹ and Q² are each O. 16.(canceled)
 17. The compound of claim 1, or a pharmaceutically acceptablesalt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein L is —CH₂CH₂—.
 18. Thecompound of claim 1, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, wherein the moiety -Q¹-L-Q²-R² is —OCH₂CH₂OCF₃ or—NR¹⁵CH₂CH₂OCF₃.
 19. The compound of claim 9, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein the moiety -Q¹-L-Q²-R² is—OCH₂CH₂OCF₃.
 20. The compound of claim 1, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein X¹ is O.
 21. The compound ofclaim 1, or a pharmaceutically acceptable salt, isotopically enrichedanalog, stereoisomer, mixture of stereoisomers, or prodrug thereof,wherein R³ is C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, or heteroaryl, eachof which is optionally substituted with one to five R¹¹.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt, isotopicallyenriched analog, stereoisomer, mixture of stereoisomers, or prodrugthereof, wherein R³ is C₃₋₁₀ cycloalkyl, aryl, or heteroaryl, each ofwhich is optionally substituted with one to five R¹¹.
 23. The compoundof claim 1, or a pharmaceutically acceptable salt, isotopically enrichedanalog, stereoisomer, mixture of stereoisomers, or prodrug thereof,wherein R³ is aryl or heteroaryl, each of which is optionallysubstituted with one to five R¹¹.
 24. The compound of claim 19, or apharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R³is aryl or heteroaryl, each of which is optionally substituted with oneto five R¹¹.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein R³ is aryl or heteroaryl,each of which is optionally substituted with chloro, fluoro, —CF₃, or acombination thereof.
 26. The compound of claim 1, or a pharmaceuticallyacceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein R³ is, or

each of which is optionally substituted with one to five R¹¹. 27-29.(canceled)
 30. The compound of claim 1, or a pharmaceutically acceptablesalt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, or prodrug thereof, wherein R⁴ and R⁵ are hydrogen. 31.The compound of claim 1, or a pharmaceutically acceptable salt,isotopically enriched analog, stereoisomer, mixture of stereoisomers, orprodrug thereof, wherein R¹ is hydrogen.
 32. A compound or apharmaceutically acceptable salt, isotopically enriched analog,stereoisomer, mixture of stereoisomers, or prodrug thereof selected fromthe group consisting of:


33. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or prodrug thereof, and a pharmaceutically acceptablecarrier.
 34. A method for treating a disease or condition mediated, atleast in part, by eukaryotic initiation factor 2B, the method comprisingadministering an effective amount of the pharmaceutical composition ofclaim 33 to a subject in need thereof.
 35. (canceled)
 36. The method ofclaim 34, wherein the disease is Alexander's disease, Alper's disease,Alzheimer's disease, amyotrophic lateral sclerosis, ataxiatelangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiformencephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasaldegeneration, Creutzfeldt-Jakob disease, frontotemporal dementia,Gerstmann-Straussler-Scheinker syndrome, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewybody dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3),Multiple sclerosis, Multiple System Atrophy, narcolepsy,Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease,Pick's disease, primary lateral sclerosis, Prion diseases, Refsum'sdisease, Sandhoffs disease, Schilder's disease, Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia,schizophrenia, Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, vanishing white matter (VWM) disease, insulin resistance orTabes dorsalis.
 37. The method of claim 34, wherein the disease isamyotrophic lateral sclerosis (ALS). 38-46. (canceled)